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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 University, School of Science and Technology. 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 responses2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 24828Article in journal (Refereed)
    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 University, School of Medical Sciences. 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 mice2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 10, p. 1974-1984Article in journal (Refereed)
    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 University, School of Medical Sciences. 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 individuals2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 106, no 2, p. 383-389, article id S0168-8227(14)00319-2Article in journal (Refereed)
    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 University, School of Medical Sciences. 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 disease2013In: Interface Focus, ISSN 2042-8898, E-ISSN 2042-8901, Vol. 3, no 2, article id 20120072Article in journal (Refereed)
    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 University, School of Medical Sciences. 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 Remission2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0126401Article in journal (Refereed)
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 vitro2011In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 7, no 2, p. 437-446Article in journal (Refereed)
    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 approaches2013In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, no 2, p. 833-846Article in journal (Refereed)
    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 University, School of Medical Sciences. 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 function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    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.
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 challenge2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 9, p. 4169-4179Article in journal (Refereed)
    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.

  • 10.
    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 University, School of Medical Sciences. 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 bread2011In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 10, article id 116Article in journal (Refereed)
    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.

  • 11.
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 risk2014In: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 58, no 9, p. 1873-1882Article in journal (Refereed)
    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.

  • 12.
    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 University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. 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 Plasma2017In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 12, p. 2275-2288Article in journal (Refereed)
    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.

  • 13.
    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 University, School of Medical Sciences. 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 profiling2012In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, no 2, p. 850-60Article in journal (Refereed)
    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.

  • 14.
    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 University, School of Medical Sciences. 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 metabolism2013In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 94, p. 279-288, article id S1874-3919(13)00511-3Article in journal (Refereed)
    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.

  • 15.
    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 University, School of Medical Sciences. 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 study2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, no 1, article id 334Article in journal (Refereed)
    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.

  • 16.
    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 University, School of Medical Sciences. 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 guidelines2018In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, no 10, p. 2001-2017Article in journal (Refereed)
    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.

  • 17.
    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 metabolism2016In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, no 3, p. 474-481Article in journal (Refereed)
    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.

  • 18.
    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 University, School of Medical Sciences. 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 obesity2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 11, p. 3697-3708Article in journal (Refereed)
    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.

  • 19.
    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 spectrometry2011In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 8, p. 3058-3067Article in journal (Refereed)
    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.

  • 20.
    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 distributions2011In: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 5, article id 175Article in journal (Refereed)
    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.

  • 21.
    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 discovery2012In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, no 4, article id 37Article, review/survey (Refereed)
    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.

  • 22.
    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 University, School of Science and Technology.
    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 University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 22, p. 2673-2683Article in journal (Refereed)
    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.

  • 23.
    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 Epithelium2017In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 12, article id E2559Article in journal (Refereed)
    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.

  • 24.
    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 University, School of Medical Sciences. 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 hypertrophy2012In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 59, no 1, p. 76-84Article in journal (Refereed)
    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.

  • 25.
    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 participants2015In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 64, no 10, p. 1348-58Article in journal (Refereed)
    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.

  • 26.
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 project2018In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 50, p. 40-46Article in journal (Refereed)
    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.

  • 27.
    Geng, Dawei
    et al.
    Örebro University, School of Science and Technology.
    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 University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo2019In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 170, p. 691-698Article in journal (Refereed)
    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.

  • 28.
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 mice2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e110359Article in journal (Refereed)
    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.

  • 29.
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 membranes2018In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 84, no 5, p. 726-732Article in journal (Refereed)
    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.

  • 30.
    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 University, School of Medical Sciences. 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 arrhythmia2011In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 92, no 1, p. 29-38Article in journal (Refereed)
    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.

  • 31.
    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 University, School of Medical Sciences. 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 cardiomyopathy2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, no 5, p. 635-642Article in journal (Refereed)
    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.

  • 32.
    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 University, School of Medical Sciences. 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 state2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 40, p. 31011-31023Article in journal (Refereed)
    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.

  • 33.
    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 University, School of Medical Sciences. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Characterization of cerebrospinal fluid by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry2013In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1293, p. 142-149, article id S0021-9673(13)00567-0Article in journal (Refereed)
    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.

  • 34.
    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 University, School of Science and Technology. 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 Drosophila2013In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 4, article id e1003438Article in journal (Refereed)
    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.

  • 35.
    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 University, School of Science and Technology. 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 progression2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 9, p. 3236-45Article in journal (Refereed)
    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.

  • 36.
    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 University, School of Science and Technology. 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 University, School of Medical Sciences. 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 patients2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 7, p. 1725-1733Article in journal (Refereed)
    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.

  • 37.
    Hogh, K-Lynn N.
    et al.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Craig, Michael N.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Uy, Christopher E.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Asadi, Ali
    Department of Cellular and Physiological Sciences and Faculty of Medicine, University of British Columbia, Vancouver BC, Canada.
    Speck, Madeline
    Child and Family Research Institute, Vancouver BC, Canada.
    Fraser, Jordie D.
    Rudecki, Alexander P.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Baker, Robert K.
    Department of Cellular and Physiological Sciences and Faculty of Medicine, University of British Columbia, Vancouver BC, Canada.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Gray, Sarah L.
    Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
    Overexpression of PPARγ specifically in pancreatic β-cells exacerbates obesity-induced glucose intolerance, reduces β-cell mass, and alters islet lipid metabolism in male mice2014In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, no 10, p. 3843-3852Article in journal (Refereed)
    Abstract [en]

    The contribution of peroxisomal proliferator-activated receptor (PPAR)-γ agonism in pancreatic β-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic β-cell PPARγ ablation have revealed a potential role for PPARγ in β-cell expansion in obesity but a limited role in normal β-cell physiology. Here we overexpressed PPARγ1 or PPARγ2 specifically in pancreatic β-cells of mice subjected to high-fat feeding using an associated adenovirus (β-PPARγ1-HFD and β-PPARγ2-HFD mice). We show β-cell-specific PPARγ1 or PPARγ2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased β-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice (β-eGFP-HFD mice). Analysis of islet lipid composition in β-PPARγ2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly β-PPARγ2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in β-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and β-oxidation. In summary, transgenic overexpression of PPARγ in β-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of β-oxidative genes, and reduced β-cell mass.

  • 38.
    Hohl, Mathias
    et al.
    Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
    Ardehali, Hossein
    Feinberg Cardiovascular Research Institute, Northwestern University, Chicago IL, United States.
    Azuaje, Francisco J
    CRP-Santé, NorLux Neuro-Oncology Laboratory, Luxembourg, Luxembourg.
    Breckenridge, Ross A
    Division of Medicine, University College London, London, United Kingdom.
    Doehner, Wolfram
    Center for Stroke Research Berlin, Charite Universitätsmedizin Berlin, Berlin, Germany.
    Eaton, Philip
    Cardiovascular Division, Rayne Institute, King's College London, London, United Kingdom.
    Ehret, Georg B
    Département de Spécialités de Médecine Interne, Service de Cardiologie, Hôpitaux Universitaires de Genève, Suisse, Switzerland.
    Fujita, Toshiro
    RCAST, University of Tokyo, Tokyo, Japan.
    Gaetani, Roberto
    Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.
    Giacca, Mauro
    Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
    Hasenfuß, Gerd
    Department of Cardiology and Pneumology, University Medical Centre, Göttingen, Germany.
    Heymans, Stephane
    Department of Cardiology, Maastricht University, Maastricht, Netherlands.
    Leite-Moreira, Adelino F
    Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
    Linke, Wolfgang A.
    Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
    Linz, Dominik
    Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
    Lyon, Alexander
    NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Imperial College, London, United Kingdom.
    Mamas, Mamas A.
    Cardiovascular Research Group, Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Papp, Zoltán
    Division of Clinical Physiology, University of Debrecen, Debrecen, Hungary.
    Pedrazzini, Thierry
    Experimental Cardiology Unit, Department of Medicine, University of Lausanne, Lausanne, Switzerland.
    Piepoli, Massimo
    Heart Failure Unit, Cardiac Department, Guglielmo da Saliceto Polichirurgico Hospital, Piacenza, Italy.
    Prosser, Benjamin
    Department of Physiology, Center of Biomedical Engineering and Technology, University of Maryland, Baltimore MD, United States.
    Rizzuto, Rosario
    Department of Biomedical Sciences, CNR Neuroscience Institute, University of Padua, Padova, Italy.
    Tarone, Guido
    Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
    Tian, Rong
    Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle WA, United States.
    van Craenenbroeck, Emeline
    Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium.
    van Rooij, Eva
    Hubrecht Institute, KNAW, University Medical Center Utrecht, Utrecht, Netherlands.
    Wai, Timothy
    Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associ. Diseases (CECAD), University of Cologne, Cologne, Germany.
    Weiss, Günter
    Department of Internal Medicine VI, Medical University, Innsbruck, Austria.
    Maack, Christoph
    Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
    Meeting highlights from the 2013 European Society of Cardiology Heart Failure Association Winter Meeting on Translational Heart Failure Research2014In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 16, no 1, p. 6-14Article in journal (Refereed)
  • 39.
    Hukkanen, J.
    et al.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Puurunen, J.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Hyötyläinen, Tuulia
    Steno Diabetes Center, Gentofte, Denmark.
    Savolainen, M. J.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Ruokonen, A.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Morin-Papunen, L.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Oresic, Matej
    Steno Diabetes Center, Gentofte, Denmark.
    Piltonen, T.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Tapanainen, J. S.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland; University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland.
    The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity2015In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 80, no 3, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

    Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20mg day1 (n=15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α- epoxycholesterol ratios were used as negative controls.

    Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference – 0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α- epoxycholesterol to cholesterol did not change.

    Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity.

    Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the

    conditions with altered cholesterol concentrations.

  • 40.
    Huopaniemi, Ilkka
    et al.
    School of Science and Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland; Helsinki Institute for Information Techology HIIT, Helsinki, Finland.
    Suvitaival, Tommi
    School of Science and Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland; Helsinki Institute for Information Techology HIIT, Helsinki, Finland.
    Nikkilä, Janne
    School of Science and Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland; Helsinki Institute for Information Techology HIIT, Helsinki, Finland; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kaski, Samuel
    School of Science and Technology, Department of Information and Computer Science, Aalto University, Espoo, Finland; Helsinki Institute for Information Techology HIIT, Helsinki, Finland.
    Multivariate multi-way analysis of multi-source data2010In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 26, no 12, p. i391-i398Article in journal (Refereed)
    Abstract [en]

    MOTIVATION: Analysis of variance (ANOVA)-type methods are the default tool for the analysis of data with multiple covariates. These tools have been generalized to the multivariate analysis of high-throughput biological datasets, where the main challenge is the problem of small sample size and high dimensionality. However, the existing multi-way analysis methods are not designed for the currently increasingly important experiments where data is obtained from multiple sources. Common examples of such settings include integrated analysis of metabolic and gene expression profiles, or metabolic profiles from several tissues in our case, in a controlled multi-way experimental setup where disease status, medical treatment, gender and time-series are usual covariates.

    RESULTS: We extend the applicability area of multivariate, multi-way ANOVA-type methods to multi-source cases by introducing a novel Bayesian model. The method is capable of finding covariate-related dependencies between the sources. It assumes the measurements consist of groups of similarly behaving variables, and estimates the multivariate covariate effects and their interaction effects for the discovered groups of variables. In particular, the method partitions the effects to those shared between the sources and to source-specific ones. The method is specifically designed for datasets with small sample sizes and high dimensionality. We apply the method to a lipidomics dataset from a lung cancer study with two-way experimental setup, where measurements from several tissues with mostly distinct lipids have been taken. The method is also directly applicable to gene expression and proteomics.

    AVAILABILITY: An R-implementation is available at http://www.cis.hut.fi/projects/mi/software/multiWayCCA/.

  • 41.
    Hyysalo, Jenni
    et al.
    Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bian, Hua
    Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Leivonen, Marja
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Jaser, Nabil
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Juuti, Anne
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Honka, Miikka-Juhani
    Turku PET Centre, University of Turku, Turku, Finland.
    Nuutila, Pirjo
    Turku PET Centre, University of Turku, Turku, Finland.
    Olkkonen, Vesa M.
    Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Circulating triacylglycerol signatures in nonalcoholic fatty liver disease associated with the I148M variant in PNPLA3 and with obesity2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 1, p. 312-322Article in journal (Refereed)
    Abstract [en]

    We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3(I148M) gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3(I148M) gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3(148MM/148MI) compared with the PNPLA3(148II) group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulin-resistant. Liver fat was similarly increased in obese and PNPLA3(148MM/148MI) groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3(I148M) versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

  • 42.
    Hyötyläinen, Tuulia
    et al.
    Örebro University, School of Science and Technology. Department of Chemistry.
    Ahonen, Linda
    Steno Diabetes Center A/S, Gentofte, Denmark .
    Pöhö, Päivi
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Lipidomics in biomedical research-practical considerations2017In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1862, no 8, p. 800-803Article in journal (Refereed)
    Abstract [en]

    Lipids have many central physiological roles including as structural components of cell membranes, energy storage sources and intermediates in signaling pathways. Lipid-related disturbances are known to underlie many diseases and their co-morbidities. The emergence of lipidomics has empowered researchers to study lipid metabolism at the cellular as well as physiological levels at a greater depth than was previously possible. The key challenges ahead in the field of lipidomics in medical research lie in the development of experimental protocols and in silico techniques needed to study lipidomes at the systems level. Clinical questions where lipidomics may have an impact in healthcare settings also need to be identified, both from the health outcomes and health economics perspectives. This article is part of a Special Issue entitled: BBALIP_Lipidomics Opinion Articles edited by Sepp Kohlwein.

  • 43.
    Hyötyläinen, Tuulia
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bondia-Pons, I.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lipidomics in nutrition and food research2013In: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 57, no 8, p. 1306-1318Article, review/survey (Refereed)
    Abstract [en]

    Lipids are a diverse class ofmetabolites that play several key roles in the maintenance of human health. Lipidomics, which focuses on the global study of molecular lipids in cells, tissues, and biofluids, has been advancing rapidly over the past decade. Recent developments in MS and computational methods enable the lipid analysis with high throughput, resolution, sensitivity, and ability for structural identification of several hundreds of lipids. In nutrition research, lipidomics can be effectively used to elucidate the interactions between diet, nutrients, and human metabolism. Lipidomics can also be applied to optimize the effects of food processing on the dietary value, and in the evaluation of food-related health effects.

  • 44.
    Hyötyläinen, Tuulia
    et al.
    Örebro University, School of Science and Technology. Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Jerby, Livnat
    Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
    Petäjä, Elina M.
    Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Mattila, Ismo
    Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Jäntti, Sirkku
    VTT Technical Research Centre of Finland, Espoo, Finland; Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Auvinen, Petri
    Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of Helsinki, Helsinki, Finland.
    Gastaldelli, Amalia
    Institute of Clinical Physiology, National Research Council, Pisa, Italy.
    Yki-Järvinen, Hannele
    Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Ruppin, Eytan
    Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel; Center for BioInformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, USA.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 8994Article in journal (Refereed)
    Abstract [en]

    Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.

  • 45.
    Hyötyläinen, Tuulia
    et al.
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland .
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Wiedmer, Susanne K
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Koivuniemi, Artturi
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Taskinen, Marja-Riitta
    Department of Medicine, University of Helsinki,Helsinki, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, University of Helsinki,Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland .
    Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance2012In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 8, no 10, p. 2559-2565Article in journal (Refereed)
    Abstract [en]

    While the molecular lipid composition of lipoproteins has been investigated in detail, little is known about associations of small polar metabolites with specific lipoproteins. The aim of the present study was to investigate the profiles of polar metabolites in different lipoprotein fractions, i.e., very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and two sub-fractions of the high-density lipoprotein (HDL). The VLDL, IDL, LDL, HDL(2), and HDL(3) fractions were isolated from serum of sixteen individuals having a broad range of insulin sensitivity and characterized using comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOFMS). The lipoprotein fractions had clearly different metabolite profiles, which correlated with the particle size and surface charge. Lipoprotein-specific associations of individual metabolites with insulin resistance were identified, particularly in VLDL and IDL fractions, even in the absence of such associations in serum. The results indicate that the polar molecules are strongly attached to the surface of the lipoproteins. Furthermore, strong lipoprotein-specific associations of metabolites with insulin resistance, as compared to their serum profiles, indicate that lipoproteins may be a rich source of tissue-specific metabolic biomarkers.

  • 46.
    Hyötyläinen, Tuulia
    et al.
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
    Oresic, Matej
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
    Optimizing the lipidomics workflow for clinical studies: practical considerations2015In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 407, no 17, p. 4973-4993, article id 8633Article, review/survey (Refereed)
    Abstract [en]

    Lipidomics is increasingly being used in clinical research, offering new opportunities for disease prediction and detection. One of the key challenges of clinical applications of lipidomics is the high sensitivity of measured lipid levels to many analytical, physiological, and environmental factors, which therefore must be taken into account when designing the studies. Here we critically discuss the complete clinical lipidomics workflow, including selection of the subjects, the sample type, the sample preprocessing conditions, and the analytical method and methods for data processing. We also review the lipidomics applications which investigate the confounding factors such as age, gender, fasting time, and handling procedures for measuring blood lipid metabolites.

  • 47.
    Hyötyläinen, Tuulia
    et al.
    Steno Diabetes Center, Gentofte, Denmark.
    Oresic, Matej
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Systems biology strategies to study lipidomes in health and disease2014In: Progress in lipid research, ISSN 0163-7827, E-ISSN 1873-2194, Vol. 55, no 1, p. 43-60Article, review/survey (Refereed)
    Abstract [en]

    Lipids are a diverse group of metabolites that have many key biological functions, acting as structural components of cell membranes, energy storage sources and intermediates in signaling pathways. Due to their importance lipids are under tight homeostatic control and exhibit spatial and dynamic complexity at multiple levels. It is thus not surprising that altered lipid metabolism plays important roles in the pathogenesis of most of the common diseases. Lipidomics emerged as a discipline which is dedicated to global study of lipidomes, including pathways and networks of lipids in biological systems. When studying the lipidomes at a systems level, one of the key challenges is how to address the lipid functionality at many physiological levels, from metabolic and signaling pathways to spatial systems such as cellular membranes and lipoprotein particles. Besides the better analytical techniques to study lipids, computational techniques have started to emerge which enable modeling of lipidomes in their spatial and dynamic context. Together, the recent methodological advances in lipidomics have a potential to open novel avenues for predictive and preventive medicine. This review focuses on progress in systems approaches to study lipids in health and disease, with specific emphasis on clinical applications.

  • 48.
    Hyötyläinen, Tuulia
    et al.
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland; Turku Centre for Biotechnology, University of Turku ,Turku, Finland.
    Orešič, Matej
    Steno Diabetes Center, Gentofte, Denmark;Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland; Turku Centre for Biotechnology, University of Turku ,Turku, Finland.
    Analytical Lipidomics in Metabolic and Clinical Research2015In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 26, no 12, p. 671-673Article in journal (Refereed)
    Abstract [en]

    Lipidomic analysis, which enables comprehensive characterization of molecular lipids in biological systems, is rapidly becoming an essential tool in biomedical research. While lipidomics already have contributed to several conceptual advances in metabolic research and led to new, validated disease biomarkers, its translation into the clinic remains a challenge.

  • 49.
    Hyötyläinen, Tuulia
    et al.
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Orešič, Matej
    Steno Diabetes Center, Gentofte, Denmark; Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Bioanalytical techniques in nontargeted clinical lipidomics2016In: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 8, no 4, p. 351-364Article in journal (Refereed)
    Abstract [en]

    Lipidomic analysis aims at comprehensive characterization of molecular lipids in biological systems. Due to the central role of lipid metabolism in many devastating diseases, lipidomics is being increasingly applied in biomedical research. Over the past years, advances in analytical techniques and bioinformatics enabled increasingly comprehensive and accurate coverage of lipids both in tissues and biofluids, yet many challenges remain. This review highlights recent progress in the domain of analytical lipidomics, with main emphasis on non-targeted methodologies for large scale clinical applications, as well as discusses some of the key challenges and opportunities in this field.

  • 50.
    Jauhiainen, Tiina A.
    et al.
    Institute of Biomedicine Pharmacology, University of Helsinki, Helsinki, Finland; Research and Development, Valio Ltd, Helsinki, Finland.
    Niittynen, Leena H.
    Nutritionist Leena Niittynen, Vihti, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Järvenpää, Salme K.
    Medcare Foundation, Änekoski, Finland.
    Hiltunen, Timo P.
    Department of Medicine and Research Program for Molecular Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    Rönnback, Mats
    Doctagon Ltd, Helsinki, Finland.
    Vapaatalo, Heikki I.
    Institute of Biomedicine Pharmacology, University of Helsinki, Helsinki, Finland.
    Korpela, Riitta A.
    Institute of Biomedicine Pharmacology, University of Helsinki, Helsinki, Finland.
    Effects of long-term intake of lactotripeptides on cardiovascular risk factors in hypertensive subjects2012In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 66, no 7, p. 843-849Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVES: Lactobacillus helveticus LBK-16H-fermented milk products containing tripeptides isoleucine-proline-proline and valine-proline-proline lower blood pressure in hypertensive subjects using office and home blood pressure registration. The present study was aimed to evaluate the effects of two doses of these lactotripeptides on 24-h ambulatory blood pressure and lipidomics profiles in mildly hypertensive subjects.

    SUBJECTS/METHODS: In a randomized, double-blind, placebo-controlled parallel group study, 89 mildly hypertensive subjects ingested, after a 1-month run-in period, a fermented milk drink with 5 mg per day of lactotripeptides during 3 months, and a milk drink with 50 mg per day of lactotripeptides for the following 3 months, or a placebo milk drink without lactotripeptides. Ambulatory blood pressure (24 h) was recorded at baseline and at the end of the intervention periods. Lipidomics profiles were characterized before and after the 6-month intervention.

    RESULTS: After the second intervention period (50 mg per day of lactotripeptides), systolic and diastolic 24-h blood pressures decreased significantly in the peptide, but not in the placebo group. However, the treatment effects -2.6 mm Hg (95% confidence interval (CI): -5.7 to 0.4) in systolic and -1.3 mm Hg (95% CI: -3.4 to 0.8) in diastolic blood pressure did not reach statistic significance. Ingestion of 5 mg per day of lactotripeptides for 3 months did not lower blood pressure. The peptide group was dominated by decrease in multiple phospholipids (PL).

    CONCLUSIONS: Ingestion of fermented milk with daily dose of 50 mg of lactotripeptides appears to lower elevated blood pressure slightly from the baseline, but not significantly compared with the placebo group and to induce significant decreases in multiple PL.

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