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  • 1.
    Aho, Vilma
    et al.
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Ollila, Hanna M
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Stanford University Center for Sleep Sciences, Palo Alto CA, United States.
    Kronholm, Erkki
    Department of Chronic Disease Prevention, Population Studies Unit, National Institute for Health and Welfare, Turku, Finland.
    Bondia-Pons, Isabel
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Soininen, Pasi
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Kangas, Antti J
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppälä, Ilkka
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Kettunen, Johannes
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Oikonen, Mervi
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
    Raitoharju, Emma
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Kähönen, Mika
    Department of Clinical Physiology, University of Tampere, Tampere University Hospital, Tampere, Finland.
    Viikari, Jorma S A
    Department of Medicine, University of Turku, Turku, Finland; Division of Medicine, Turku University Hospital, Turku, Finland.
    Härmä, Mikko
    Brain and Work Research Centre, Finnish Institute of Occupational Health, Helsinki, Finland.
    Sallinen, Mikael
    Brain and Work Research Centre, Finnish Institute of Occupational Health, Helsinki, Finland; Agora Center, University of Jyväskylä, Jyväskylä, Finland.
    Olkkonen, Vesa M
    Minerva Foundation Institute for Medical Research, Helsinki, Finland; Institute of Biomedicine, Anatomy, University of Helsinki, Helsinki, Finland.
    Alenius, Harri
    Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
    Jauhiainen, Matti
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland.
    Paunio, Tiina
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    Lehtimäki, Terho
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Salomaa, Veikko
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Raitakari, Olli T
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
    Ala-Korpela, Mika
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Oulu University Hospital, Oulu, Finland; Computational Medicine, School of Social and Community Medicine, Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Porkka-Heiskanen, Tarja
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 24828Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

  • 2.
    Ahola-Erkkilä, Sofia
    et al.
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Carroll, Christopher J.
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Peltola-Mjösund, Katja
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tulkki, Valtteri
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Tyynismaa, Henna
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Suomalainen, Anu
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki, University Central Hospital, Helsinki, Finland.
    Ketogenic diet slows down mitochondrial myopathy progression in mice2010Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, nr 10, s. 1974-1984Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.

  • 3.
    Andersen, Gregers Stig Tig
    et al.
    Steno Diabetes Center, Gentofte, Denmark.
    Thybo, Tanja
    Steno Diabetes Center, Gentofte, Denmark.
    Cederberg, Henna
    Department of Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Steno Diabetes Center, Gentofte, Denmark.
    Esteller, Manel B.
    Cancer Epigenetics and Biology Program, Spanish Biomedical Research Centre Network for Epidemiology and Public Health, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Barcelona, Spain.
    Zorzano, Antonio
    Institute for Research in Biomedicine, Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Carr, Bernadette M.
    Voluntary Health Insurance Board, Dublin, Ireland.
    Walker, Mark G.
    University of Newcastle-on-Tyne, Newcastle, United Kingdom.
    Cobb, Jeff E.
    Metabolon Inc., Durham NC, United States.
    Clissmann, C.
    Pintail Ltd., Dublin, Ireland.
    O'Gorman, Donal J.
    Centre for Preventive Medicine, School of Health and Human Performance, Dublin City University, Dublin, Ireland.
    Nolan, John J.
    Steno Diabetes Center, Gentofte, Denmark.
    The DEXLIFE study methods: identifying novel candidate biomarkers that predict progression to type 2 diabetes in high risk individuals2014Inngår i: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 106, nr 2, s. 383-389, artikkel-id S0168-8227(14)00319-2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.

  • 4.
    Antila, Kari
    et al.
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Lötjönen, Jyrki
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Thurfjell, Lennart
    GE Healthcare, Stockholm, Sweden.
    Laine, Jarmo
    Nexstim Ltd, Helsinki, Finland.
    Massimini, Marcello
    University of Milan, Milan, Italy.
    Rueckert, Daniel
    Imperial College London, London, United Kingdom.
    Zubarev, Roman A.
    Karolinska Institutet, Stockholm, Sweden.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Tampere, Finland.
    van Gils, Mark
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Mattila, Jussi
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Hviid Simonsen, Anja
    Rigshospitalet, Copenhagen, Denmark.
    Waldemar, Gunhild
    Rigshospitalet, Copenhagen, Denmark.
    Soininen, Hilkka
    University of Eastern Finland, Kuopio, Finland.
    The PredictAD project: development of novel biomarkers and analysis software for early diagnosis of the Alzheimer's disease2013Inngår i: Interface Focus, ISSN 2042-8898, E-ISSN 2042-8901, Vol. 3, nr 2, artikkel-id 20120072Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alzheimer's disease (AD) is the most common cause of dementia affecting 36 million people worldwide. As the demographic transition in the developed countries progresses towards older population, the worsening ratio of workers per retirees and the growing number of patients with age-related illnesses such as AD will challenge the current healthcare systems and national economies. For these reasons AD has been identified as a health priority, and various methods for diagnosis and many candidates for therapies are under intense research. Even though there is currently no cure for AD, its effects can be managed. Today the significance of early and precise diagnosis of AD is emphasized in order to minimize its irreversible effects on the nervous system. When new drugs and therapies enter the market it is also vital to effectively identify the right candidates to benefit from these. The main objective of the PredictAD project was to find and integrate efficient biomarkers from heterogeneous patient data to make early diagnosis and to monitor the progress of AD in a more efficient, reliable and objective manner. The project focused on discovering biomarkers from biomolecular data, electrophysiological measurements of the brain and structural, functional and molecular brain images. We also designed and built a statistical model and a framework for exploiting these biomarkers with other available patient history and background data. We were able to discover several potential novel biomarker candidates and implement the framework in software. The results are currently used in several research projects, licensed to commercial use and being tested for clinical use in several trials.

  • 5.
    Arora, Tulika
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espoo, Finland; Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, Helsinki, Finland.
    Pournaras, Dimitri J.
    Department of Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.
    Welbourn, Richard
    Department of Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.
    le Roux, Carel W.
    Diabetes Complications Research Centre, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Gastrosurgical Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicie, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, University of Copenhagen, Copenhagen, Denmark.
    Roux-en-Y Gastric Bypass Surgery Induces Early Plasma Metabolomic and Lipidomic Alterations in Humans Associated with Diabetes Remission2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0126401Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Roux-en-Y gastric bypass (RYGB) is an effective method to attain sustained weight loss and diabetes remission. We aimed to elucidate early changes in the plasma metabolome and lipidome after RYGB. Plasma samples from 16 insulin-resistant morbidly obese subjects, of whom 14 had diabetes, were subjected to global metabolomics and lipidomics analysis at pre-surgery and 4 and 42 days after RYGB. Metabolites and lipid species were compared between time points and between subjects who were in remission and not in remission from diabetes 2 years after surgery. We found that the variables that were most discriminatory between time points were decanoic acid and octanoic acid, which were elevated 42 days after surgery, and sphingomyelins (18:1/21:0 and 18:1/23:3), which were at their lowest level 42 days after surgery. Insulin levels were lower at 4 and 42 days after surgery compared with pre-surgery levels. At 4 days after surgery, insulin levels correlated positively with metabolites of branched chain and aromatic amino acid metabolism and negatively with triglycerides with long-chain fatty acids. Of the 14 subjects with diabetes prior to surgery, 7 were in remission 2 years after surgery. The subjects in remission displayed higher pre-surgery levels of tricarboxylic acid cycle intermediates and triglycerides with long-chain fatty acids compared with subjects not in remission. Thus, metabolic alterations are induced soon after surgery and subjects with diabetes remission differ in the metabolic profiles at pre- and early post-surgery time points compared to patients not in remission.

  • 6.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bounsaythip, Catherine
    University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Oksman-Caldentey, Kirsi-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Drug metabolome of the simvastatin formed by human intestinal microbiota in vitro2011Inngår i: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 7, nr 2, s. 437-446Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human colon contains a diverse microbial population which contributes to degradation and metabolism of food components. Drug metabolism in the colon is generally poorly understood. Metabolomics techniques and in vitro colon models are now available which afford detailed characterization of drug metabolites in the context of colon metabolism. The aim of this work was to identify novel drug metabolites of Simvastatin (SV) by using an anaerobic human in vitro colon model at body temperature coupled with systems biology platform, excluding the metabolism of the host liver and intestinal epithelia. Comprehensive two-dimensional gas chromatography with a time-of-flight mass spectrometry (GC×GC-TOFMS) was used for the metabolomic analysis. Metabolites showing the most significant differences in the active faecal suspension were elucidated in reference with SV fragmentation and compared with controls: inactive suspension or buffer with SV, or with active suspension alone. Finally, time courses of selected metabolites were investigated. Our data suggest that SV is degraded by hydrolytic cleavage of methylbutanoic acid from the SV backbone. Metabolism involves demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and β-oxidation resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclisation of heptanoic acid (possibly de-esterified and cleaved methylpyranyl arm) to produce cyclohexanecarboxylic acid. Our study elucidates a pathway of colonic microbial metabolism of SV as well as demonstrates the applicability of the in vitro colon model and metabolomics to the discovery of novel drug metabolites from drug response profiles.

  • 7.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Cheynier, Veronique
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Souquet, Jean-Marc
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Bes, Magali
    Unité Expérimentale de Pech Rouge, Institut national de la recherche agronomique (INRA), Gruissan, France.
    Le Bourvellec, Carine
    Sécurité et Qualité des Produits d'Origine Végétale, Institut national de la recherche agronomique (INRA), Avignon, France.
    Guyot, Sylvain
    Cidricoles et Biotransformation des Fruits et Légumes, Institut national de la recherche agronomique (INRA), Le Rheu, France.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Characterization of microbial metabolism of Syrah grape products in an in vitro colon model using targeted and non-targeted analytical approaches2013Inngår i: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, nr 2, s. 833-846Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Syrah red grapes are used in the production of tannin-rich red wines. Tannins are high molecular weight molecules, proanthocyanidins (PAs), and poorly absorbed in the upper intestine. In this study, gut microbial metabolism of Syrah grape phenolic compounds was investigated.

    METHODS: Syrah grape pericarp was subjected to an enzymatic in vitro digestion model, and red wine and grape skin PA fraction were prepared. Microbial conversion was screened using an in vitro colon model with faecal microbiota, by measurement of short-chain fatty acids by gas chromatography (GC) and microbial phenolic metabolites using GC with mass detection (GC-MS). Red wine metabolites were further profiled using two-dimensional GC mass spectrometry (GCxGC-TOFMS). In addition, the effect of PA structure and dose on conversion efficiency was investigated by GC-MS.

    RESULTS: Red wine exhibited a higher degree of C1-C3 phenolic acid formation than PA fraction or grape pericarp powders. Hydroxyphenyl valeric acid (flavanols and PAs as precursors) and 3,5-dimethoxy-4-hydroxybenzoic acid (anthocyanin as a precursor) were identified from the red wine metabolite profile. In the absence of native grape pericarp or red wine matrix, the isolated PAs were found to be effective in the dose-dependent inhibition of microbial conversions and short-chain fatty acid formation.

    CONCLUSIONS: Metabolite profiling was complementary to targeted analysis. The identified metabolites had biological relevance, because the structures of the metabolites resembled fragments of their grape phenolic precursors or were in agreement with literature data.

  • 8.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 4, s. 1180-1192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

  • 9.
    Beger, Richard D.
    et al.
    Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, USA.
    Dunn, Warwick
    School of Biosciences, Phenome Centre Birmingham and Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK.
    Schmidt, Michael A.
    Advanced Pattern Analysis and Countermeasures Group, Research Innovation Center, Colorado State University, Fort Collins, USA.
    Gross, Steven S.
    Department of Pharmacology, Weill Cornell Medical College, New York, USA.
    Kirwan, Jennifer A.
    School of Biosciences, University of Birmingham, Birmingham, UK.
    Cascante, Marta
    Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Brennan, Lorraine
    UCD Institute of Food and Health, UCD, Belfield, Ireland.
    Wishart, David S.
    Departments of Computing Science and Biological Sciences, University of Alberta, Edmonton, Canada.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Hankemeier, Thomas
    Division of Analytical Biosciences and Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University & Netherlands Metabolomics Centre, Leiden, The Netherlands.
    Broadhurst, David I.
    School of Science, Edith Cowan University, Perth, Australia.
    Lane, Andrew N.
    Center for Environmental Systems Biochemistry, Department Toxicology and Cancer Biology, Markey Cancer Center, Lexington, USA.
    Suhre, Karsten
    Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar.
    Kastenmüller, Gabi
    Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, Oberschleißheim, Germany.
    Sumner, Susan J.
    Discovery Sciences, RTI International, Research Triangle Park, Durham, USA.
    Thiele, Ines
    University of Luxembourg, Luxembourg Centre for Systems Biomedicine, Campus Belval, Esch-Sur-Alzette, Luxembourg.
    Fiehn, Oliver
    West Coast Metabolomics Center, UC Davis, Davis, USA; Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia.
    Kaddurah-Daouk, Rima
    Psychiatry and Behavioral Sciences, Duke Internal Medicine and Duke Institute for Brain Sciences and Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, USA.
    Metabolomics enables precision medicine: "A White Paper, Community Perspective"2016Inngår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, nr 10, artikkel-id 149Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.

    OBJECTIVES OF WHITE PAPER—EXPECTED TREATMENT OUTCOMES AND METABOLOMICS ENABLING TOOL FOR PRECISION MEDICINE: We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject's response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient's metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.

    CONCLUSIONS KEY SCIENTIFIC CONCEPTS AND RECOMMENDATIONS FOR PRECISION MEDICINE: Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its "Precision Medicine and Pharmacometabolomics Task Group", with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

  • 10.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, University of Navarra, Pamplona, Spain.
    Maukonen, Johanna
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rissanen, Aila
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
    Saarela, Maria
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kaprio, Jaakko
    Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
    Hakkarainen, Antti
    Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Jesper
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Nina
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Pietiläinen, Kirsi H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge2014Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, nr 9, s. 4169-4179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels.

  • 11.
    Bondia-Pons, Isabel
    et al.
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland.
    Nordlund, Emilia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Katina, Kati
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Aura, Anna-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kolehmainen, Marjukka
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Mykkänen, Hannu
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland.
    Poutanen, Kaisa
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Postprandial differences in the plasma metabolome of healthy Finnish subjects after intake of a sourdough fermented endosperm rye bread versus white wheat bread2011Inngår i: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 10, artikkel-id 116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The mechanism behind the lowered postprandial insulin demand observed after rye bread intake compared to wheat bread is unknown. The aim of this study was to use the metabolomics approach to identify potential metabolites related to amino acid metabolism involved in this mechanism.

    METHODS: A sourdough fermented endosperm rye bread (RB) and a standard white wheat bread (WB) as a reference were served in random order to 16 healthy subjects. Test bread portions contained 50 g available carbohydrate. In vitro hydrolysis of starch and protein were performed for both test breads. Blood samples for measuring glucose and insulin concentrations were drawn over 4 h and gastric emptying rate (GER) was measured. Changes in the plasma metabolome were investigated by applying a comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics platform (GC × GC-TOF-MS).

    RESULTS: Plasma insulin response to RB was lower than to WB at 30 min (P = 0.004), 45 min (P = 0.002) and 60 min (P < 0.001) after bread intake, and plasma glucose response was significantly higher at time point 90 min after RB than WB intake (P = 0.045). The starch hydrolysis rate was higher for RB than WB, contrary to the in vitro protein digestibility. There were no differences in GER between breads. From 255 metabolites identified by the metabolomics platform, 26 showed significant postprandial relative changes after 30 minutes of bread intake (p and q values < 0.05). Among them, there were changes in essential amino acids (phenylalanine, methionine, tyrosine and glutamic acid), metabolites involved in the tricarboxylic acid cycle (alpha-ketoglutaric, pyruvic acid and citric acid) and several organic acids. Interestingly, the levels of two compounds involved in the tryptophan metabolism (picolinic acid, ribitol) significantly changed depending on the different bread intake.

    CONCLUSIONS: A single meal of a low fibre sourdough rye bread producing low postprandial insulin response brings in several changes in plasma amino acids and their metabolites and some of these might have properties beneficial for health.

  • 12.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, Research Building, University of Navarra, Pamplona, Spain.
    Pöhö, Päivi
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bozzetto, Lutgarda
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Vetrani, Claudia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Patti, Lidia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Aura, Anna-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Annuzzi, Giovanni
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Rivellese, Angela Albarosa
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Isoenergetic diets differing in their n-3 fatty acid and polyphenol content reflect different plasma and HDL-fraction lipidomic profiles in subjects at high cardiovascular risk2014Inngår i: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 58, nr 9, s. 1873-1882Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    SCOPE: Dysregulation of lipid homeostasis is related to multiple major healthcare problems. The aim of this study was to investigate the effects of n-3 fatty acid (FA) and polyphenol rich diets on plasma and HDL fraction lipidomic profiles in subjects at high cardiovascular risk.

    METHODS AND RESULTS: Ultra performance LC coupled to quadrupole TOF/MS mass spectrometry global lipidomic profiling was applied to plasma and HDL fraction from an 8 wk randomized intervention with four isoenergetic diets, differing in their natural n-3 FA and polyphenols content, in 78 subjects with a high BMI, abdominal obesity, and at least one other feature of the metabolic syndrome. Dependency network analysis showed a different pattern of associations between lipidomics, dietary, and clinical variables after the dietary interventions. The most remarkable associations between variables were observed after the diet high in n-3 FA and polyphenols, as the inverse association between gallic acid intake and LDL cholesterol levels, which was indirectly associated with a HDL cluster exclusively comprised lysophospholipids.

    CONCLUSION: This is the first human randomized controlled trial showing direct and indirect associations with lipid molecular species and clinical variables of interest in the evaluation of the metabolic syndrome after diets naturally rich in polyphenols.

  • 13.
    Bowden, John A.
    et al.
    Marine Biochemical Sciences Group, Chemical Sciences Division, Hollings Marine Laboratory, National Institute of Standards and Technology, Charleston SC, USA.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Hollings Marine Laboratory, Marine Biochemical Sciences Group, National Institute of Standards and Technology, Charleston SC, United States; Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta GA, United States.
    Zhou, Senlin
    Department of Chemistry and Biochemistry, Wayne State University, Detroit MI, USA.
    Harmonizing Lipidomics: NIST Interlaboratory Comparison Exercise for Lipidomics using Standard Reference Material 1950 Metabolites in Frozen Human Plasma2017Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, nr 12, s. 2275-2288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950 Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each lab using a different lipidomics workflow. A total of 1527 unique lipids were measured across all laboratories, and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and inter-laboratory quality control and method validation. These analyses were performed using non-standardized laboratory-independent workflows. The consensus locations were also compared to a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

  • 14.
    Brockmöller, Scarlet F.
    et al.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Bucher, Elmar
    Medical Biotechnology, VTT Technical Research Centre of Finland, University of Turku, Turku, Finland.
    Müller, Berit M.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Budczies, Jan
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Iljin, Kristiina
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Darb-Esfahani, Silvia
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Sinn, Bruno V.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Prinzler, Judith
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Bangemann, Nikola
    Breast Cancer Center, Charité University Hospital, Berlin, Germany.
    Ismaeel, Fakher
    Department of Gynaecology and Obstetrics, DRK Kliniken Köpenick, Berlin, Germany; Department of Gynaecology and Obstetrics, Charité University Hospital, Berlin, Germany.
    Fiehn, Oliver
    Genome Center, University of California-Davis, Davis CA, United States.
    Dietel, Manfred
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Integration of metabolomics and expression of glycerol-3-phosphate acyltransferase (GPAM) in breast cancer-link to patient survival, hormone receptor status, and metabolic profiling2012Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, nr 2, s. 850-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes in lipid metabolism are an important but not well-characterized hallmark of cancer. On the basis of our recent findings of lipidomic changes in breast cancer, we investigated glycerol-3-phosphate acyltransferase (GPAM), a key enzyme in the lipid biosynthesis of triacylglycerols and phospholipids. GPAM protein expression was evaluated and linked to metabolomic and lipidomic profiles in a cohort of human breast carcinomas. In addition, GPAM mRNA expression was analyzed using the GeneSapiens in silico transcriptiomics database. High cytoplasmic GPAM expression was associated with hormone receptor negative status (p = 0.013). On the protein (p = 0.048) and mRNA (p = 0.001) levels, increased GPAM expression was associated with a better overall survival. Metabolomic analysis by GC-MS showed that sn-glycerol-3-phosphate, the substrate of GPAM, was elevated in breast cancer compared to normal breast tissue. LC-MS based lipidomic analysis identified significantly higher levels of phospholipids, especially phosphatidylcholines in GPAM protein positive tumors. In conclusion, our results suggest that GPAM is expressed in human breast cancer with associated changes in the cellular metabolism, in particular an increased synthesis of phospholipids, the major structural component of cellular membranes.

  • 15.
    Budczies, Jan
    et al.
    Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Brockmöller, Scarlet F.
    Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
    Müller, Berit M.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Barupal, Dinesh K.
    International Agency for Research on Cancer (IARC), Lyon, France.
    Richter-Ehrenstein, Christiane
    Interdisciplinary Breast Center, Charité University Hospital, Berlin, Germany.
    Kleine-Tebbe, Anke
    Breast Center, DRK Kliniken Berlin, Berlin, Germany.
    Griffin, Julian L.
    Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
    Dietel, Manfred
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Fiehn, Oliver
    Genome Center, University of California Davis, Davis CA, United States.
    Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism2013Inngår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 94, s. 279-288, artikkel-id S1874-3919(13)00511-3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    UNLABELLED: Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER-) breast cancer tissues were investigated using GC-TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER- subtype. Beta-alanine demonstrated the strongest change between ER- and ER+ breast cancer (fold change=2.4, p=1.5E-20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R=-0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER- breast cancer. In a Kaplan-Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR=0.6, p=3.2E-15).

    BIOLOGICAL SIGNIFICANCE: It is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER- breast as different diseases requiring different treatment strategies. Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER- breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER- subtype as a preferential target for glutaminase inhibitors. For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER- breast cancer.

  • 16.
    Budczies, Jan
    et al.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Müller, Berit M.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Brockmöller, Scarlet F.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Györffy, Balazs
    Institute of Pathology, Charité University Hospital, Berlin, Germany; Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Dietel, Manfred
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Richter-Ehrenstein, Christiane
    Interdisciplinary Breast Center, Charité University Hospital, Berlin, Germany.
    Marten, Ulrike
    Institute of Pathology, DRK Kliniken Berlin, Berlin, Germany.
    Salek, Reza M.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Wohlgemuth, Gert
    Genome Center, University of California Davis, Davis CA, United States.
    Fiehn, Oliver
    Genome Center, University of California Davis, Davis CA, United States.
    Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue - a GC-TOFMS based metabolomics study2012Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, nr 1, artikkel-id 334Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Changes in energy metabolism of the cells are common to many kinds of tumors and are considered a hallmark of cancer. Gas chromatography followed by time-of-flight mass spectrometry (GC-TOFMS) is a well-suited technique to investigate the small molecules in the central metabolic pathways. However, the metabolic changes between invasive carcinoma and normal breast tissues were not investigated in a large cohort of breast cancer samples so far.

    RESULTS: A cohort of 271 breast cancer and 98 normal tissue samples was investigated using GC-TOFMS-based metabolomics. A total number of 468 metabolite peaks could be detected; out of these 368 (79%) were significantly changed between cancer and normal tissues (p<0.05 in training and validation set). Furthermore, 13 tumor and 7 normal tissue markers were identified that separated cancer from normal tissues with a sensitivity and a specificity of >80%. Two-metabolite classifiers, constructed as ratios of the tumor and normal tissues markers, separated cancer from normal tissues with high sensitivity and specificity. Specifically, the cytidine-5-monophosphate / pentadecanoic acid metabolic ratio was the most significant discriminator between cancer and normal tissues and allowed detection of cancer with a sensitivity of 94.8% and a specificity of 93.9%.

    CONCLUSIONS: For the first time, a comprehensive metabolic map of breast cancer was constructed by GC-TOF analysis of a large cohort of breast cancer and normal tissues. Furthermore, our results demonstrate that spectrometry-based approaches have the potential to contribute to the analysis of biopsies or clinical tissue samples complementary to histopathology.

  • 17.
    Burla, Bo
    et al.
    Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore.
    Arita, Makoto
    Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan; Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, Tokyo, Japan.
    Arita, Masanori
    National Institute of Genetics, Shizuoka, Japan and RIKEN Center for Sustainable Resource Science, Yokohama, Japan.
    Bendt, Anne K.
    Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore.
    Cazenave-Gassiot, Amaury
    Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    Dennis, Edward A.
    Departments of Pharmacology and Chemistry and Biochemistry, School of Medicine, University of California at San Diego, La Jolla, CA, USA.
    Ekroos, Kim
    Lipidomics Consulting Ltd., Esbo, Finland.
    Han, Xianlin
    Barshop Institute for Longevity and Aging Studies and Department of Medicine-Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
    Ikeda, Kazutaka
    Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
    Liebisch, Gerhard
    Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
    Lin, Michelle K.
    Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    Loh, Tze Ping
    Department of Laboratory Medicine, National University Hospital, Singapore.
    Meikle, Peter J.
    Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    Orešič, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Quehenberger, Oswald
    Departments of Pharmacology and Medicine, School of Medicine, University of California at San Diego, La Jolla, CA, USA.
    Shevchenko, Andrej
    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
    Torta, Federico
    Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    Wakelam, Michael J. O.
    Babraham Institute, Cambridge, United Kingdom.
    Wheelock, Craig E.
    Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Wenk, Markus R.
    Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore; Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines2018Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, nr 10, s. 2001-2017Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human blood is a self-regenerating lipid-rich biological fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers insights into individual metabolism and physiology in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on MS is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.

  • 18.
    Caesar, Robert
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism2016Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, nr 3, s. 474-481Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.

  • 19.
    Carobbio, Stefania
    et al.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Hagen, Rachel M.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lelliott, Christopher J.
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Slawik, Marc
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Endocrine Research Unit, Medizinische Klinik-Innenstadt, Ludwig-Maximilians University, Munich, Germany.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, , Madrid, Spain.
    Tan, Chong-Yew
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Sicard, Audrey
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France.
    Atherton, Helen J.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Barbarroja, Nuria
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Hospital Virgen de la Victoria, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Malaga, Spain.
    Bjursell, Mikael
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Bohlooly-Y, Mohammad
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Virtue, Sam
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Tuthill, Antoinette
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lefai, Etienne
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Laville, Martine
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Wu, Tingting
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Considine, Robert V.
    Division of Endocrinology and Metabolism, School of Medicine, Indiana University, Indianapolis IN, United States.
    Vidal, Hubert
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Langin, Dominique
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France; Laboratory of Clinical Biochemistry, Toulouse, France.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medicine, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
    Tinahones, Francisco J.
    Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
    Fernandez-Real, Jose Manuel
    Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain.
    Griffin, Julian L.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Sethi, Jaswinder K.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    López, Miguel
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity2013Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 11, s. 3697-3708Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

  • 20.
    Castillo, S.
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, I.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Miettinen, J.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Data analysis tool for comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry2011Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, nr 8, s. 3058-3067Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Data processing and identification of unknown compounds in comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC x GC/TOFMS) analysis is a major challenge, particularly when large sample sets are analyzed. Herein, we present a method for efficient treatment of large data sets produced by GC x GC/TOFMS implemented as a freely available open source software package, Guineu. To handle large data sets and to efficiently utilize all the features available in the vendor software (baseline correction, mass spectral deconvolution, peak picking, integration, library search, and signal-to-noise filtering), data preprocessed by instrument software are used as a starting point for further processing. Our software affords alignment of the data, normalization, data filtering, and utilization of retention indexes in the verification of identification as well as a novel tool for automated group-type identification of the compounds. Herein, different features of the software are studied in detail and the performance of the system is verified by the analysis of a large set of standard samples as well as of a large set of authentic biological samples, including the control samples. The quantitative features of our GC x GC/TOFMS methodology are also studied to further demonstrate the method performance and the experimental results confirm the reliability of the developed procedure. The methodology has already been successfully used for the analysis of several thousand samples in the field of metabolomics.

  • 21.
    Clish, Clary B.
    et al.
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Davidov, Eugene
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Oresic, Matej
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Plasterer, Thomas N.
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Lavine, Gary
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Londo, Tom
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Meys, Michael
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Snell, Philip
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Stochaj, Wayne
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Adourian, Aram
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Zhang, Xiang
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Morel, Nicole
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Neumann, Eric
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Verheij, Elwin
    TNO Pharma, Zeist, Netherlands.
    Vogels, Jack T. W. E.
    TNO Pharma, Zeist, Netherlands.
    Havekes, Louis M.
    TNO Prevention and Health, Gaubius Laboratorium, Leiden, Netherlands; Departments of Cardiology and Internal Medicine and Leiden Center for Cardiovascular Research, Leiden University Medical Center, Leiden, Netherlands.
    Afeyan, Noubar
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Regnier, Fred
    Department of Chemistry, Purdue University, Lafayette, Indiana, USA.
    van der Greef, Jan
    Beyond Genomics, Inc., Waltham, Massachusetts, USA; TNO Pharma, Zeist, Netherlands; Division of Analytical Biosciences, Leiden/Amsterdam Centre for Drug Research, Leiden University, Leiden, Netherlands.
    Naylor, Stephen
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Integrative biological analysis of the APOE*3-leiden transgenic mouse2004Inngår i: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 8, nr 1, s. 3-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalian disease model, the apolipoprotein E3-Leiden (APO*E3) transgenic mouse. Mice selected for the study were fed a normal chow diet and sacrificed at 9 weeks of age-conditions under which they develop only mild type I and II atherosclerotic lesions. Hepatic mRNA expression analysis showed a 25% decrease in APO A1 and a 43% increase in liver fatty acid binding protein expression between transgenic and wild type control mice, while there was no change in PPAR-alpha expression. On-line high performance liquid chromatography-mass spectrometry quantitative profiling of tryptic digests of soluble liver proteins and liver lipids, coupled with principle component analysis, enabled rapid identification of early protein and metabolite markers of disease pathology. These included a 44% increase in L-FABP in transgenic animals compared to controls, as well as an increase in triglycerides and select bioactive lysophosphatidylcholine species. A correlation analysis of identified genes, proteins, and lipids was used to construct an interaction network. Taken together, these results indicate that integrative biology is a powerful tool for rapid identification of early markers and key components of pathophysiologic processes, and constitute the first application of this approach to a mammalian system.

  • 22.
    Curtis, R. Keira
    et al.
    University of Cambridge Department of Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Hills Road, Cambridge, UK.
    Oresic, Matej
    Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland.
    Vidal-Puig, Antonio
    University of Cambridge Department of Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Hills Road, Cambridge, UK.
    Pathways to the analysis of microarray data2005Inngår i: Trends in Biotechnology, ISSN 0167-7799, E-ISSN 1879-3096, Vol. 23, nr 8, s. 429-435Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The development of microarray technology allows the simultaneous measurement of the expression of many thousands of genes. The information gained offers an unprecedented opportunity to fully characterize biological processes. However, this challenge will only be successful if new tools for the efficient integration and interpretation of large datasets are available. One of these tools, pathway analysis, involves looking for consistent but subtle changes in gene expression by incorporating either pathway or functional annotations. We review several methods of pathway analysis and compare the performance of three, the binomial distribution, z scores, and gene set enrichment analysis, on two microarray datasets. Pathway analysis is a promising tool to identify the mechanisms that underlie diseases, adaptive physiological compensatory responses and new avenues for investigation.

  • 23.
    Davidov, Eugene
    et al.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Clish, Clary B.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Oresic, Matej
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Meys, Michael
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Stochaj, Wayne
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Snell, Philip
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Lavine, Gary
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Londo, Thomas R.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Adourian, Aram
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Zhang, Xiang
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Johnston, Mark
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Morel, Nicole
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Marple, Edward W.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Plasterer, Thomas N.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Neumann, Eric
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Verheij, Elwin
    TNO Pharma, Zeist, The Netherlands.
    Vogels, Jack T. W. E.
    TNO Pharma, Zeist, The Netherlands.
    Havekes, Louis M.
    TNO Prevention and Health, Gaubius Laboratorium, Leiden, The Netherlands; Departments of Cardiology and Internal Medicine and Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
    van der Greef, Jan
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA; TNO Pharma, Zeist, The Netherlands; Departments of Cardiology and Internal Medicine and Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
    Naylor, Stephen
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Methods for the differential integrative omic analysis of plasma from a transgenic disease animal model2004Inngår i: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 8, nr 4, s. 267-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multitiered quantitative analysis of biological systems is rapidly becoming the desired approach to study hierarchical functional interactions between proteins and metabolites. We describe here a novel systematic approach to analyze organisms with complex metabolic regulatory networks. By using precise analytical methods to measure biochemical constituents and their relative abundance in whole plasma of transgenic ApoE*3-Leiden mice and an isogenic wild-type control group, simultaneous snapshots of metabolic and protein states were obtained. Novel data processing and multivariate analysis tools such as Impurity Resolution Software (IMPRESS) and Windows-based linear fit program (WINLIN) were used to compare protein and metabolic profiles in parallel. Canonical correlations of the resulting data show quantitative relationships between heterogeneous components in the TG animals. These results, obtained solely from whole plasma analysis allowed us, in a rapid manner, to corroborate previous findings as well as find new events pertaining to dominant and peripheral events in lipoprotein metabolism of a genetically modified mammalian organism in relation to ApoE3, a key mediator of lipoprotein metabolism.

  • 24.
    de Mas, Igor Marin
    et al.
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain;; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Selivanov, Vitaly A.
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain; A.N.Belozersky Institute of Physico-Chemical Biology, Moscow, Russia.
    Marin, Silvia
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain;; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Roca, Josep
    Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS),Centro de Investigación Biomédica en Red de Enfermedade Respiratorias (CIBERES) Universitat de Barcelona, Barcelona, Spain.
    Oresic, Matej
    Technical Research Centre of Finland, Espoo, Finland; Institute for Molecular Medicine, Helsinki, Finland.
    Agius, Loranne
    Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, UK.
    Cascante, Marta
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions2011Inngår i: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 5, artikkel-id 175Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution.

    RESULTS: The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate). The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells.

    CONCLUSIONS: The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose phosphates in cytosol. In contrast, the observed distribution indicates the presence of a separate pool of hexose phosphates that is channeled towards glycogen synthesis.

  • 25.
    de Mello, V. D. F.
    et al.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Lankinen, M.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Schwab, U.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kolehmainen, M.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Lehto, S.
    Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Seppänen-Laakso, T.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Pulkkinen, L.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Uusitupa, M
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Erkkilä, A. T.
    Department of Public Health, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease2009Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, nr 12, s. 2612-2615Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS/HYPOTHESIS: Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD.

    METHODS: Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index).

    RESULTS: Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001).

    CONCLUSIONS/INTERPRETATION: Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.

  • 26.
    de Mello, Vanessa D. F.
    et al.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Erkkilä, Arja T.
    Department of Public Health, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Schwab, Ursula S.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Pulkkinen, Leena
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Kolehmainen, Marjukka
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Atalay, Mustafa
    Department of Physiology, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Mussalo, Hanna
    Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
    Lankinen, Maria
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lehto, Seppo
    Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Uusitupa, Matti
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    The effect of fatty or lean fish intake on inflammatory gene expression in peripheral blood mononuclear cells of patients with coronary heart disease2009Inngår i: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 48, nr 8, s. 447-455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Little is known about the effect of fish consumption on gene expression of inflammation-related genes in immune cells in coronary heart disease (CHD).

    AIM OF THE STUDY: We sought to evaluate the effect of a fatty fish (FF) or a lean fish (LF) diet on the modulation of inflammatory and endothelial function-related genes in peripheral blood mononuclear cells (PBMCs) of subjects with CHD, and its association with serum fatty acid (FA) profile and lipid metabolic compounds.

    METHODS: Data from 27 patients randomized into an 8-week FF (n = 10; mean +/- SD: 4.3 +/- 0.4 portions of fish per week), LF (n = 11; 4.7 +/- 1.1 portions of fish per week), or control diet (n = 6; 0.6 +/- 0.4 portions of fish per week) were analyzed. The mRNA expression was measured using real-time PCR.

    RESULTS: The effect of the intervention on the mRNA expression of the genes studied did not differ among groups. In the FF group, however, the decrease in arachidonic acid to eicosapentaenoic acid (AA:EPA) ratio in cholesterol ester and phospholipid fractions strongly correlated with the change in IL1B mRNA levels (r (s) = 0.60, P = 0.06 and r (s) = 0.86, P = 0.002, respectively). In the LF group, the decrease in palmitic acid and total saturated FAs in cholesterol esters correlated with the change in intercellular cell adhesion molecule-1 (ICAM1) expression (r (s) = 0.64, P = 0.04 for both). Circulating levels of soluble ICAM-1 decreased only in the LF group (P < 0.05).

    CONCLUSIONS: The intake of FF or LF diet did not alter the expression of inflammatory and endothelial function-related genes in PBMCs of patients with CHD. However, the decrease in AA:EPA ratio in serum lipids in the FF group may induce an anti-inflammatory response at mRNA levels in PBMCs. A LF diet might benefit endothelial function, possibly mediated by the changes in serum FA composition.

  • 27.
    Denkert, Carsten
    et al.
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Bucher, Elmar
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Hilvo, Mika
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Salek, Reza
    Department of Biochemistry, University of Cambridge, Cambridge, UK.
    Oresic, Matej
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Griffin, Julian
    Department of Biochemistry, University of Cambridge, Cambridge, UK.
    Brockmöller, Scarlet
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Barupal, Dinesh Kumar
    Genome Center, University of California, Davis CA, USA.
    Budczies, Jan
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Iljin, Kristiina
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Nekljudova, Valentina
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Fiehn, Oliver
    Genome Center, University of California, Davis CA, USA.
    Metabolomics of human breast cancer: new approaches for tumor typing and biomarker discovery2012Inngår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, nr 4, artikkel-id 37Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Breast cancer is the most common cancer in women worldwide, and the development of new technologies for better understanding of the molecular changes involved in breast cancer progression is essential. Metabolic changes precede overt phenotypic changes, because cellular regulation ultimately affects the use of small-molecule substrates for cell division, growth or environmental changes such as hypoxia. Differences in metabolism between normal cells and cancer cells have been identified. Because small alterations in enzyme concentrations or activities can cause large changes in overall metabolite levels, the metabolome can be regarded as the amplified output of a biological system. The metabolome coverage in human breast cancer tissues can be maximized by combining different technologies for metabolic profiling. Researchers are investigating alterations in the steady state concentrations of metabolites that reflect amplified changes in genetic control of metabolism. Metabolomic results can be used to classify breast cancer on the basis of tumor biology, to identify new prognostic and predictive markers and to discover new targets for future therapeutic interventions. Here, we examine recent results, including those from the European FP7 project METAcancer consortium, that show that integrated metabolomic analyses can provide information on the stage, subtype and grade of breast tumors and give mechanistic insights. We predict an intensified use of metabolomic screens in clinical and preclinical studies focusing on the onset and progression of tumor development.

  • 28.
    Dickens, Alex Mountfort
    et al.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland .
    Posti, Jussi P.
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland .
    Takala, Riikka Sk.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland .
    Ala-Seppälä, Henna Maria
    Department of Neurology,University of Turku, Turku, Finland .
    Mattila, Ismo
    Steno Diabetes Center AS, Gentofte, Denmark.
    Coles, Jonathan Coles
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Frantzén, Janek
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery,Turku University Hospital, Turku, Finland .
    Hutchinson, Peter John
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Katila, Ari J.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
    Kyllönen, Anna
    Department of Neurology, University of Turku, Turku, Finland .
    Maanpää, Henna-Riikka
    Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland.
    Newcombe, Virginia
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Norther Ireland.
    Outtrim, Joanne
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Tallus, Jussi
    Division of Anaesthesia, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Carpenter, Keri
    Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Menon, David
    Head, Division of Anaesthesia, Addenbrooke's Hospital, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Tenovuo, Olli
    Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland .
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury2018Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, nr 22, s. 2673-2683Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.

  • 29.
    Duszka, Kalina
    et al.
    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; Center for Integrative Genomics, University of Lausanne, Génopode, Lausanne, Switzerland; Department of Nutritional Sciences, University of Vienna, Vienna, Austria.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University,Turku, Finland.
    Le May, Cedric
    Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.
    König, Jürgen
    Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria.
    Wahli, Walter
    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; Center for Integrative Genomics, University of Lausanne Génopode, Lausanne, Switzerland; ToxAlim, Research Center in Food Toxicology, National Institute for Agricultural Research (INRA), Toulouse, France.
    PPARγ Modulates Long Chain Fatty Acid Processing in the Intestinal Epithelium2017Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, nr 12, artikkel-id E2559Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nuclear receptor PPARγ affects lipid metabolism in several tissues, but its role in intestinal lipid metabolism has not been explored. As alterations have been observed in the plasma lipid profile of ad libitum fed intestinal epithelium-specific PPARγ knockout mice (iePPARγKO), we submitted these mice to lipid gavage challenges. Within hours after gavage with long chain unsaturated fatty acid (FA)-rich canola oil, the iePPARγKO mice had higher plasma free FA levels and lower gastric inhibitory polypeptide levels than their wild-type (WT) littermates, and altered expression of incretin genes and lipid metabolism-associated genes in the intestinal epithelium. Gavage with the medium chain saturated FA-rich coconut oil did not result in differences between the two genotypes. Furthermore, the iePPARγKO mice did not exhibit defective lipid uptake and stomach emptying; however, their intestinal transit was more rapid than in WT mice. When fed a canola oil-rich diet for 4.5 months, iePPARγKO mice had higher body lean mass than the WT mice. We conclude that intestinal epithelium PPARγ is activated preferentially by long chain unsaturated FAs compared to medium chain saturated FAs. Furthermore, we hypothesize that the iePPARγKO phenotype originates from altered lipid metabolism and release in epithelial cells, as well as changes in intestinal motility.

  • 30.
    Elo, Laura L.
    et al.
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland.
    Järvenpää, Henna
    Turku Centre for Biotechnology, Turku, Finland.
    Oresic, Matej
    Turku Centre for Biotechnology, Turku, Finland; VTT Biotechnology, Espoo, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, Turku, Finland.
    Aittokallio, Tero
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland; Systems Biology Unit, Institut Pasteur, Paris, France.
    Systematic construction of gene coexpression networks with applications to human T helper cell differentiation process2007Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 23, nr 16, s. 2096-2103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MOTIVATION: Coexpression networks have recently emerged as a novel holistic approach to microarray data analysis and interpretation. Choosing an appropriate cutoff threshold, above which a gene-gene interaction is considered as relevant, is a critical task in most network-centric applications, especially when two or more networks are being compared.

    RESULTS: We demonstrate that the performance of traditional approaches, which are based on a pre-defined cutoff or significance level, can vary drastically depending on the type of data and application. Therefore, we introduce a systematic procedure for estimating a cutoff threshold of coexpression networks directly from their topological properties. Both synthetic and real datasets show clear benefits of our data-driven approach under various practical circumstances. In particular, the procedure provides a robust estimate of individual degree distributions, even from multiple microarray studies performed with different array platforms or experimental designs, which can be used to discriminate the corresponding phenotypes. Application to human T helper cell differentiation process provides useful insights into the components and interactions controlling this process, many of which would have remained unidentified on the basis of expression change alone. Moreover, several human-mouse orthologs showed conserved topological changes in both systems, suggesting their potential importance in the differentiation process.

    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

  • 31.
    Elo, Laura L.
    et al.
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland.
    Katajamaa, Mikko
    Turku Centre for Biotechnology, Turku, Finland.
    Lund, Riikka
    Turku Centre for Biotechnology, Turku, Finland.
    Oresic, Matej
    Turku Centre for Biotechnology, Turku, Finland; VTT Biotechnology, Espoo, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, Turku, Finland.
    Aittokallio, Tero
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland; Systems Biology Unit, Institut Pasteur, Paris, France.
    Improving identification of differentially expressed genes by integrative analysis of Affymetrix and Illumina arrays2006Inngår i: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 10, nr 3, s. 369-380Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Together with the widely used Affymetrix microarrays, the recently introduced Illumina platform has become a cost-effective alternative for genome-wide studies. To efficiently use data from both array platforms, there is a pressing need for methods that allow systematic integration of multiple datasets, especially when the number of samples is small. To address these needs, we introduce a meta-analytic procedure for combining Affymetrix and Illumina data in the context of detecting differentially expressed genes between the platforms. We first investigate the effect of different expression change estimation procedures within the platforms on the agreement of the most differentially expressed genes. Using the best estimation methods, we then show the benefits of the integrative analysis in producing reproducible results across bootstrap samples. In particular, we demonstrate its biological relevance in identifying small but consistent changes during T helper 2 cell differentiation.

  • 32.
    Finckenberg, Piet
    et al.
    Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Eriksson, Ove
    Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Baumann, Marc
    Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Merasto, Saara
    Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Lalowski, Maciej M.
    Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Levijoki, Jouko
    Orion Pharma Ltd, Espoo, Finland.
    Haasio, Kristiina
    Orion Pharma Ltd, Espoo, Finland.
    Kytö, Ville
    Department of Medicine, Turku University Hospital, Turku, Finland.
    Muller, Dominik N.
    Experimental and Clinical Research Center, Max Delbrück Center, Berlin, Germany.
    Luft, Friedrich C.
    Experimental and Clinical Research Center, Max Delbrück Center, Berlin, Germany.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Mervaala, Eero
    Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Caloric restriction ameliorates angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy2012Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 59, nr 1, s. 76-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiotensin II-induced cardiac damage is associated with oxidative stress-dependent mitochondrial dysfunction. Caloric restriction (CR), a dietary regimen that increases mitochondrial activity and cellular stress resistance, could provide protection. We tested that hypothesis in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs). CR (60% of energy intake for 4 weeks) decreased mortality in dTGRs. CR ameliorated angiotensin II-induced cardiomyocyte hypertrophy, vascular inflammation, cardiac damage and fibrosis, cardiomyocyte apoptosis, and cardiac atrial natriuretic peptide mRNA overexpression. The effects were blood pressure independent and were linked to increased endoplasmic reticulum stress, autophagy, serum adiponectin level, and 5' AMP-activated protein kinase phosphorylation. CR decreased cardiac p38 phosphorylation, nitrotyrosine expression, and serum insulin-like growth factor 1 levels. Mitochondria from dTGR hearts showed clustered mitochondrial patterns, decreased numbers, and volume fractions but increased trans-sectional areas. All of these effects were reduced in CR dTGRs. Mitochondrial proteomic profiling identified 43 dTGR proteins and 42 Sprague-Dawley proteins, of which 29 proteins were in common in response to CR. We identified 7 proteins in CR dTGRs that were not found in control dTGRs. In contrast, 6 mitochondrial proteins were identified from dTGRs that were not detected in any other group. Gene ontology annotations with the Panther protein classification system revealed downregulation of cytoskeletal proteins and enzyme modulators and upregulation of oxidoreductase activity in dTGRs. CR provides powerful, blood pressure-independent, protection against angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy. The findings support the notion of modulating cardiac bioenergetics to ameliorate angiotensin II-induced cardiovascular complications.

  • 33.
    Foerster, Jana
    et al.
    Department of Epidemiology, German Institute of Human Nutrition Potsdam–Rehbruecke, Nuthetal, Germany.
    Hyötyläinen, Tuulia
    Systems Medicine, Steno Diabetes Centre, Gentofte, Denmark.
    Oresic, Matej
    Systems Medicine, Steno Diabetes Centre, Gentofte, Denmark.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam–Rehbruecke, Nuthetal, Germany.
    Serum Lipid and Serum Metabolite Components in relation to anthropometric parameters in EPIC-Potsdam participants2015Inngår i: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 64, nr 10, s. 1348-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND/AIM: Lipidomic and metabolomic techniques become more and more important in human health research. Recent developments in analytical techniques enable the investigation of high amounts of substances. The high numbers of metabolites and lipids that are detected with among others mass spectrometric techniques challenge in most cases the statistical processes to bring out stable and interpretable results. This study targets to use the novel non-established statistical method treelet transform (TT) to investigate high numbers of metabolites and lipids and to compare the results with the established method principal component analysis (PCA). Serum lipid and metabolite profiles are investigated regarding their association to anthropometric parameters associated to obesity.

    METHODS: From 226 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Potsdam study blood samples were investigated with an untargeted metabolomics approach regarding serum metabolites and lipids. Additionally, participants were surveyed anthropometrically to assess parameters of obesity, such as body mass index (BMI), waist-to-hip-ratio (WHR) and body fat mass. TT and PCA are used to generate treelet components (TCs) and factors summarizing serum metabolites and lipids in new, latent variables without too much loss of information. With partial correlations TCs and factors were associated to anthropometry under the control for relevant parameters, such as sex and age.

    RESULTS: TT with metabolite variables (p=121) resulted in 5 stable and interpretable TCs explaining 18.9% of the variance within the data. PCA on the same variables generated 4 quite complex, less easily interpretable factors explaining 37.5% of the variance. TT on lipidomic data (p=353) produced 3 TCs as well as PCA on the same data resulted in 3 factors; the proportion of explained variance was 17.8% for TT and 39.8% for PCA. In both investigations TT ended up with stable components that are easier to interpret than the factors from the PCA. In general, the generated TCs and factors were similar in their structure when the factors are considered regarding the original variables loading high on them. Both TCs and factors showed associations to anthropometric measures.

    CONCLUSIONS: TT is a suitable statistical method to generate summarizing, latent variables in data sets with more variables than observations. In the present investigation it resulted in similar latent variables compared to the established method of PCA. Whereby less variance is explained by the summarizing constructs of TT compared to the factors of PCA, TCs are easier to interpret. Additionally the resulting TCs are quite stable in bootstrap samples.

  • 34.
    Frank, Elisabeth
    et al.
    Biomax Informatics AB, Planegg, Germany.
    Maier, Dieter
    Biomax Informatics AB, Planegg, Germany.
    Pajula, Juha
    VTT Technical Research Centre of Finland Ltd., Tampere, Finland.
    Suvitaival, Tommi
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Borgan, Faith
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Butz-Ostendorf, Markus
    Biomax Informatics AB, Planegg, Germany.
    Fischer, Alexander
    Philips GmbH Innovative Technologies, Aachen, Germany.
    Hietala, Jarmo
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Howes, Oliver
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Chemistry, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Janssen, Joost
    Child and Adolescent Psychiatry Department, School of Medicine, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
    Laurikainen, Heikki
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Moreno, Carmen
    Child and Adolescent Psychiatry Department, School of Medicine, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
    Suvisaari, Jaana
    National Institute for Health and Welfare (THL), Helsinki, Finland.
    Van Gils, Mark
    VTT Technical Research Centre of Finland Ltd.,Tampere, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Platform for systems medicine research and diagnostic applications in psychotic disorders - The METSY project2018Inngår i: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 50, s. 40-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Psychotic disorders are associated with metabolic abnormalities including alterations in glucose and lipid metabolism. A major challenge in the treatment of psychosis is to identify patients with vulnerable metabolic profiles who may be at risk of developing cardiometabolic co-morbidities. It is established that both central and peripheral metabolic organs use lipids to control energy balance and regulate peripheral insulin sensitivity. The endocannabinoid system, implicated in the regulation of glucose and lipid metabolism, has been shown to be dysregulated in psychosis. It is currently unclear how these endocannabinoid abnormalities relate to metabolic changes in psychosis. Here we review recent research in the field of metabolic co-morbidities in psychotic disorders as well as the methods to study them and potential links to the endocannabinoid system. We also describe the bioinformatics platforms developed in the EU project METSY for the investigations of the biological etiology in patients at risk of psychosis and in first episode psychosis patients. The METSY project was established with the aim to identify and evaluate multi-modal peripheral and neuroimaging markers that may be able to predict the onset and prognosis of psychiatric and metabolic symptoms in patients at risk of developing psychosis and first episode psychosis patients. Given the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which combines molecular, structural and functional neuroimaging methods with detailed metabolic characterisation and multi-variate network analysis is essential in order to identify how lipid dysregulation may contribute to psychotic disorders. A decision support system, integrating clinical, neuropsychological and neuroimaging data, was also developed in order to aid clinical decision making in psychosis. Knowledge of common and specific mechanisms may aid the etiopathogenic understanding of psychotic and metabolic disorders, facilitate early disease detection, aid treatment selection and elucidate new targets for pharmacological treatments.

  • 35.
    Gatfield, David
    et al.
    Department of Molecular Biology, Sciences III, University of Geneva, Geneva, Switzerland.
    Le Martelot, Gwendal
    Department of Molecular Biology, Sciences III, University of Geneva, Geneva, Switzerland.
    Vejnar, Charles E.
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Swiss Institute of Bioinformatics, Geneva, Switzerland.
    Gerlach, Daniel
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Swiss Institute of Bioinformatics, Geneva, Switzerland.
    Schaad, Olivier
    Genomics Platform, University of Geneva Medical School, Geneva, Switzerland.
    Fleury-Olela, Fabienne
    Department of Molecular Biology, Sciences III, University of Geneva, Geneva, Switzerland.
    Ruskeepää, Anna-Liisa
    VTT Technical Research Centre of Finland, VTT, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, VTT, Finland.
    Esau, Christine C.
    Regulus Therapeutics, Carlsbad, California, USA.
    Zdobnov, Evgeny M.
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Swiss Institute of Bioinformatics, Geneva, Switzerland; 7Imperial College London, London, United Kingdom.
    Schibler, Ueli
    Department of Molecular Biology, Sciences III, University of Geneva, Geneva, Switzerland.
    Integration of microRNA miR-122 in hepatic circadian gene expression2009Inngår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 23, nr 11, s. 1313-26Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In liver, most metabolic pathways are under circadian control, and hundreds of protein-encoding genes are thus transcribed in a cyclic fashion. Here we show that rhythmic transcription extends to the locus specifying miR-122, a highly abundant, hepatocyte-specific microRNA. Genetic loss-of-function and gain-of-function experiments have identified the orphan nuclear receptor REV-ERBalpha as the major circadian regulator of mir-122 transcription. Although due to its long half-life mature miR-122 accumulates at nearly constant rates throughout the day, this miRNA is tightly associated with control mechanisms governing circadian gene expression. Thus, the knockdown of miR-122 expression via an antisense oligonucleotide (ASO) strategy resulted in the up- and down-regulation of hundreds of mRNAs, of which a disproportionately high fraction accumulates in a circadian fashion. miR-122 has previously been linked to the regulation of cholesterol and lipid metabolism. The transcripts associated with these pathways indeed show the strongest time point-specific changes upon miR-122 depletion. The identification of Pparbeta/delta and the peroxisome proliferator-activated receptor alpha (PPARalpha) coactivator Smarcd1/Baf60a as novel miR-122 targets suggests an involvement of the circadian metabolic regulators of the PPAR family in miR-122-mediated metabolic control.

  • 36.
    Geng, Dawei
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Musse, Ayan Au
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Wigh, Viktoria
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Carlsson, Cecilia
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Engwall, Magnus
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Scherbak, Nikolai
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo2019Inngår i: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 170, s. 691-698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid β-oxidation is suppressed while the peroxisomal fatty acid β -oxidation is increased. At higher doses, however, both β -oxidation pathways are upregulated.

  • 37.
    Gopalacharyulu, Peddinti V.
    et al.
    VTT Biotechnology, Espoo, Finland.
    Lindfors, Erno
    VTT Biotechnology, Espoo, Finland.
    Bounsaythip, Catherine
    VTT Biotechnology, Espoo, Finland.
    Kivioja, Teemu
    VTT Biotechnology, Espoo, Finland.
    Yetukuri, Laxman
    VTT Biotechnology, Espoo, Finland.
    Hollmén, Jaakko
    Helsinki University of Technology, Laboratory of Computer and Information Science, Espoo, Finland.
    Oresic, Matej
    VTT Biotechnology, Espoo, Finland.
    Data integration and visualization system for enabling conceptual biology2005Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 21 Suppl 1, s. i177-i185Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MOTIVATION: Integration of heterogeneous data in life sciences is a growing and recognized challenge. The problem is not only to enable the study of such data within the context of a biological question but also more fundamentally, how to represent the available knowledge and make it accessible for mining.

    RESULTS: Our integration approach is based on the premise that relationships between biological entities can be represented as a complex network. The context dependency is achieved by a judicious use of distance measures on these networks. The biological entities and the distances between them are mapped for the purpose of visualization into the lower dimensional space using the Sammon's mapping. The system implementation is based on a multi-tier architecture using a native XML database and a software tool for querying and visualizing complex biological networks. The functionality of our system is demonstrated with two examples: (1) A multiple pathway retrieval, in which, given a pathway name, the system finds all the relationships related to the query by checking available metabolic pathway, transcriptional, signaling, protein-protein interaction and ontology annotation resources and (2) A protein neighborhood search, in which given a protein name, the system finds all its connected entities within a specified depth. These two examples show that our system is able to conceptually traverse different databases to produce testable hypotheses and lead towards answers to complex biological questions.

  • 38.
    Gopalacharyulu, Peddinti V.
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lindfors, Erno
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Miettinen, Jarkko
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bounsaythip, Catherine K.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    An integrative approach for biological data mining and visualisation2008Inngår i: International Journal of Data Mining and Bioinformatics, ISSN 1748-5673, E-ISSN 1748-5681, Vol. 2, nr 1, s. 54-77Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The emergence of systems biology necessitates development of platforms to organise and interpret plentitude of biological data. We present a system to integrate data across multiple bioinformatics databases and enable mining across various conceptual levels of biological information. The results are represented as complex networks. Context dependent mining of these networks is achieved by use of distances. Our approach is demonstrated with three applications: full metabolic network retrieval with network topology study, exploration of properties and relationships of a set of selected proteins, and combined visualisation and exploration of gene expression data with related pathways and ontologies.

  • 39.
    Gopalacharyulu, Peddinti V.
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Velagapudi, Vidya R.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lindfors, Erno
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Halperin, Eran
    International Computer Science Institute, Berkeley, California, USA .
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Dynamic network topology changes in functional modules predict responses to oxidative stress in yeast2009Inngår i: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 5, nr 3, s. 276-287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In response to environmental challenges, biological systems respond with dynamic adaptive changes in order to maintain the functionality of the system. Such adaptations may lead to cumulative stress over time, possibly leading to global failure of the system. When studying such systems responses, it is therefore important to understand them in system-wide and dynamic context. Here we hypothesize that dynamic changes in the topology of functional modules of integrated biological networks reflect their activity under specific environmental challenges. We introduce topological enrichment analysis of functional subnetworks (TEAFS), a method for the analysis of integrated molecular profile and interactome data, which we validated by comprehensive metabolomic analysis of dynamic yeast response under oxidative stress. TEAFS identified activation of multiple stress response related mechanisms, such as lipid metabolism and phospholipid biosynthesis. We identified, among others, a fatty acid elongase IFA38 as a hub protein which was absent at all time points under oxidative stress conditions. The deletion mutant of the IFA38 encoding gene is known for the accumulation of ceramides. By applying a comprehensive metabolomic analysis, we confirmed the increased concentrations over time of ceramides and palmitic acid, a precursor of de novo ceramide biosynthesis. Our results imply that the connectivity of the system is being dynamically modulated in response to oxidative stress, progressively leading to the accumulation of (lipo)toxic lipids such as ceramides. Studies of local network topology dynamics can be used to investigate as well as predict the activity of biological processes and the system's responses to environmental challenges and interventions.

  • 40.
    Greiner, Thomas U.
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    The gut microbiota modulates glycaemic control and serum metabolite profiles in non-obese diabetic mice2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikkel-id e110359Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses.

  • 41.
    Grip, Tove
    et al.
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Dyrlund, Thomas S.
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Ahonen, Linda
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Domellöf, Magnus
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Hernell, Olle
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Chemistry.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Institute, Helsinki, Finland.
    Lönnerdal, Bo
    Department of Nutrition, University of California, Davis, United States.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Academy University, Turku, Finland.
    Timby, Niklas
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Serum, plasma and erythrocyte membrane lipidomes in infants fed formula supplemented with bovine milk fat globule membranes2018Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 84, nr 5, s. 726-732Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Supplementation of formula with bovine milk fat globule membranes has been shown to narrow the gap in immunological and cognitive development between breast-fed and formula-fed infants.

    METHOD: In a double-blinded randomized controlled trial 160 formula-fed infants received an experimental formula (EF), supplemented with bovine milk fat globule membranes, or standard formula until 6 months of age. A breast-fed reference group was recruited. Lipidomic analyses were performed on plasma and erythrocyte membranes at 6 months and on serum at 4 and 12 months of age.

    RESULTS: At 6 months of age, we observed a significant separation in the plasma lipidome between the two formula groups, mostly due to differences in concentrations of sphingomyelins (SM), phosphatidylcholines (PC), and ceramides, and in the erythrocyte membrane lipidome, mostly due to SMs, PEs and PCs. Already at 4 months, a separation in the serum lipidome was evident where SMs and PCs contributed. The separation was not detected at 12 months.

    CONCLUSIONS: The effect of MFGM supplementation on the lipidome is likely part of the mechanisms behind the positive cognitive and immunological effects of feeding the EF previously reported in the same study population.

  • 42.
    Gurung, Iman S.
    et al.
    Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Madrid, Spain.
    Kis, Adrienn
    Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
    Baker, Michael
    Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom.
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espo, Finland.
    Neogi, Sudeshna Guha
    Genomics CoreLab, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
    Campbell, Mark
    Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
    Lelliott, Christopher
    Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom; Department of Bioscience, CVGI IMED, AstraZeneca R and D, Mölndal, Sweden.
    McFarlane, Ian
    Genomics CoreLab, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espo, Finland.
    Grace, Andrew A.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom.
    Huang, Christopher L-H.
    Department of Physiology Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom.
    Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia2011Inngår i: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 92, nr 1, s. 29-38Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β(-/-) hearts potentially associated with increased arrhythmic risk in metabolic diseases.

    METHODS AND RESULTS: Microarray analysis in mouse PGC1β(-/-) hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β(-/-) mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β(-/-) hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β(-/-) ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca(2+) transients, whose amplitude and frequency were increased by isoprenaline, and Ca(2+) currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K(+) currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca(2+)-calmodulin dependent protein kinase II expression.

    CONCLUSION: PGC1β(-/-) hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca(2+) homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.

  • 43.
    Götz, Alexandra
    et al.
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tyynismaa, Henna
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Euro, Liliya
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Ellonen, Pekka
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ojala, Tiina
    Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Hämäläinen, Riikka H
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tommiska, Johanna
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g.
    Raivio, Taneli
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Karikoski, Riitta
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tammela, Outi
    Pediatric Research Centre, Tampere University Hospital, Tampere, Finland.
    Simola, Kalle O J
    Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Paetau, Anders
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tyni, Tiina
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Suomalainen, Anu
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy2011Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, nr 5, s. 635-642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

  • 44.
    Hall, Diana
    et al.
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Poussin, Carine
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Velagapudi, Vidya R.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Empsen, Christophe
    Vrije Universiteit Brussel, Brussels, Belgium.
    Joffraud, Magali
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Beckmann, Jacques S.
    Service and Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
    Geerts, Albert E.
    Vrije Universiteit Brussel, Brussels, Belgium.
    Ravussin, Yann
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Ibberson, Mark
    Service and Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; Vital-IT, Lausanne, Switzerland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Thorens, Bernard
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state2010Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 40, s. 31011-31023Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accumulation of fat in the liver increases the risk to develop fibrosis and cirrhosis and is associated with development of the metabolic syndrome. Here, to identify genes or gene pathways that may underlie the genetic susceptibility to fat accumulation in liver, we studied A/J and C57Bl/6 mice that are resistant and sensitive to diet-induced hepatosteatosis and obesity, respectively. We performed comparative transcriptomic and lipidomic analysis of the livers of both strains of mice fed a high fat diet for 2, 10, and 30 days. We found that resistance to steatosis in A/J mice was associated with the following: (i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and β-oxidation; (ii) an increased expression of the elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with these observations, peroxisomal β-oxidation was increased in livers of A/J mice, and lipidomic analysis showed increased concentrations of long chain fatty acid-containing triglycerides, arachidonic acid-containing lysophosphatidylcholine, and 2-arachidonylglycerol, a cannabinoid receptor agonist. We found that the anti-inflammatory CB2 receptor was the main hepatic cannabinoid receptor, which was highly expressed in Kupffer cells. We further found that A/J mice had a lower pro-inflammatory state as determined by lower plasma levels and IL-1β and granulocyte-CSF and reduced hepatic expression of their mRNAs, which were found only in Kupffer cells. This suggests that increased 2-arachidonylglycerol production may limit Kupffer cell activity. Collectively, our data suggest that genetic variations in the expression of peroxisomal β-oxidation genes and of genes controlling the production of an anti-inflammatory lipid may underlie the differential susceptibility to diet-induced hepatic steatosis and pro-inflammatory state.

  • 45.
    Hartonen, Minna
    et al.
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Ruskeepää, Anna-Liisa
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Characterization of cerebrospinal fluid by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry2013Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1293, s. 142-149, artikkel-id S0021-9673(13)00567-0Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-TOFMS) was applied in the quantification and identification of organic compounds in patient-matched human cerebrospinal fluid (CSF) and serum samples. Concentrations of 21 amino and hydroxyl acids varied from 0.04 to 77ng/μl in CSF and from 0.1 to 84ng/μl in serum. In total, 91 metabolites out of over 1200 detected were identified based on mass spectra and retention indices. The other metabolites were identified at the functional group level. The main metabolites detected in CSF were sugar and amino acid derivatives. The CSF and serum had clearly distinct metabolic profiles, with larger biological variation in the serum than in CSF. The GC×GC-TOFMS allowed detection and identification of several metabolites that have not been previously detected in CSF.

  • 46.
    Havula, Essi
    et al.
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Teesalu, Mari
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppälä, Heini
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Hasygar, Kiran
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Auvinen, Petri
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Sandmann, Thomas
    German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Hietakangas, Ville
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Mondo/ChREBP-Mlx-regulated transcriptional network is essential for dietary sugar tolerance in Drosophila2013Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 4, artikkel-id e1003438Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sugars are important nutrients for many animals, but are also proposed to contribute to overnutrition-derived metabolic diseases in humans. Understanding the genetic factors governing dietary sugar tolerance therefore has profound biological and medical significance. Paralogous Mondo transcription factors ChREBP and MondoA, with their common binding partner Mlx, are key sensors of intracellular glucose flux in mammals. Here we report analysis of the in vivo function of Drosophila melanogaster Mlx and its binding partner Mondo (ChREBP) in respect to tolerance to dietary sugars. Larvae lacking mlx or having reduced mondo expression show strikingly reduced survival on a diet with moderate or high levels of sucrose, glucose, and fructose. mlx null mutants display widespread changes in lipid and phospholipid profiles, signs of amino acid catabolism, as well as strongly elevated circulating glucose levels. Systematic loss-of-function analysis of Mlx target genes reveals that circulating glucose levels and dietary sugar tolerance can be genetically uncoupled: Krüppel-like transcription factor Cabut and carbonyl detoxifying enzyme Aldehyde dehydrogenase type III are essential for dietary sugar tolerance, but display no influence on circulating glucose levels. On the other hand, Phosphofructokinase 2, a regulator of the glycolysis pathway, is needed for both dietary sugar tolerance and maintenance of circulating glucose homeostasis. Furthermore, we show evidence that fatty acid synthesis, which is a highly conserved Mondo-Mlx-regulated process, does not promote dietary sugar tolerance. In contrast, survival of larvae with reduced fatty acid synthase expression is sugar-dependent. Our data demonstrate that the transcriptional network regulated by Mondo-Mlx is a critical determinant of the healthful dietary spectrum allowing Drosophila to exploit sugar-rich nutrient sources.

  • 47.
    Hernández-Alvarez, María Isabel
    et al.
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Sebastián, David
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Vives, Sara
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Ivanova, Saška
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Bartoccioni, Paola
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Kakimoto, Pamela
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
    Plana, Natalia
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Veiga, Sónia R.
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
    Hernández, Vanessa
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Vasconcelos, Nuno
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Peddinti, Gopal
    VTT Technical Research Center of Finland, Espoo, Finland.
    Adrover, Anna
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Jové, Mariona
    Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
    Pamplona, Reinald
    Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
    Gordaliza-Alaguero, Isabel
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Calvo, Enrique
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Cabré, Noemí
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
    Castro, Rui
    Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
    Kuzmanic, Antonija
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Boutant, Marie
    Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
    Sala, David
    Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Fort, Joana
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Errasti-Murugarren, Ekaitz
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Rodrígues, Cecilia M. P.
    Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
    Orozco, Modesto
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Joven, Jorge
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
    Cantó, Carles
    Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
    Palacin, Manuel
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Fernández-Veledo, Sonia
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Vendrell, Joan
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Universitat Rovira i Virgili, Tarragona, Spain.
    Zorzano, Antonio
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease2019Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, nr 4, s. 881-895.e17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.

  • 48.
    Hilvo, Mika
    et al.
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Denkert, Carsten
    Institute of Pathology, Berlin, Germany.
    Lehtinen, Laura
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Müller, Berit
    Institute of Pathology, Berlin, Germany.
    Brockmöller, Scarlet
    Institute of Pathology, Berlin, Germany.
    Seppänen-Laakso, Tuulikki
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Budczies, Jan
    Institute of Pathology, Berlin, Germany.
    Bucher, Elmar
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Yetukuri, Laxman
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Castillo, Sandra
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Berg, Emilia
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Nygren, Heli
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Sysi-Aho, Marko
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Fiehn, Oliver
    Genome Center, University of California, Davis CA, United States.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Richter-Ehrenstein, Christiane
    cBreast Cancer Center, Charité University Hospital, Berlin, Germany.
    Radke, Cornelia
    Institute of Pathology, DRK Klinikum Berlin Köpenick, Berlin, Germany.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Iljin, Kristiina
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Oresic, Matej
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression2011Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, nr 9, s. 3236-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.

  • 49.
    Hilvo, Mika
    et al.
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Gade, Stephan
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Nekljudova, Valentina
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Seppänen-Laakso, Tuulikki
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Sysi-Aho, Marko
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Untch, Michael
    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
    Huober, Jens
    Department of Gynecology, University of Ulm, Ulm, Germany.
    von Minckwitz, Gunter
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Denkert, Carsten
    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients2014Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, nr 7, s. 1725-1733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.

  • 50.
    Hiukka, Anne
    et al.
    Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland.
    Ståhlman, Marcus
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Pettersson, Camilla
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Levin, Malin
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Adiels, Martin
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Teneberg, Susanne
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Leinonen, Eeva S.
    Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland.
    Hultén, Lillemor Mattsson
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Wiklund, Olov
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Oresic, Matej
    Technical Research Centre of Finland VTT, Espoo, Finland.
    Olofsson, Sven-Olof
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Taskinen, Marja-Riitta
    Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland.
    Ekroos, Kim
    Zora Biosciences, Espoo, Finland.
    Borén, Jan
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan2009Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, nr 9, s. 2018-2026Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Apolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. We investigated potential proatherogenic properties of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes.

    RESEARCH DESIGN AND METHODS: LDL was isolated from control subjects, subjects with type 2 diabetes, and apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [(3)H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII or with LDL enriched with specific apoCIII isoforms.

    RESULTS: We showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional site A in apoB100. Our findings indicated that intrinsic characteristics of the diabetic LDL other than apoCIII are responsible for further increased proteoglycan binding of diabetic LDL with high-endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by sphingomyelinases. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content and that sialylation of apoCIII was essential for its proinflammatory properties.

    CONCLUSIONS: We have demonstrated a number of features of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes that could explain the proatherogenic role of apoCIII.

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