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

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

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

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

  • 3.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Cheynier, Veronique
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Souquet, Jean-Marc
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Bes, Magali
    Unité Expérimentale de Pech Rouge, Institut national de la recherche agronomique (INRA), Gruissan, France.
    Le Bourvellec, Carine
    Sécurité et Qualité des Produits d'Origine Végétale, Institut national de la recherche agronomique (INRA), Avignon, France.
    Guyot, Sylvain
    Cidricoles et Biotransformation des Fruits et Légumes, Institut national de la recherche agronomique (INRA), Le Rheu, France.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Characterization of microbial metabolism of Syrah grape products in an in vitro colon model using targeted and non-targeted analytical approaches2013Inngår i: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, nr 2, s. 833-846Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 4.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, University of Navarra, Pamplona, Spain.
    Maukonen, Johanna
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rissanen, Aila
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
    Saarela, Maria
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kaprio, Jaakko
    Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
    Hakkarainen, Antti
    Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Jesper
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Nina
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Pietiläinen, Kirsi H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge2014Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, nr 9, s. 4169-4179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 5.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, Research Building, University of Navarra, Pamplona, Spain.
    Pöhö, Päivi
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bozzetto, Lutgarda
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Vetrani, Claudia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Patti, Lidia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Aura, Anna-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Annuzzi, Giovanni
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Rivellese, Angela Albarosa
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Isoenergetic diets differing in their n-3 fatty acid and polyphenol content reflect different plasma and HDL-fraction lipidomic profiles in subjects at high cardiovascular risk2014Inngår i: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 58, nr 9, s. 1873-1882Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

  • 6.
    Bowden, John A.
    et al.
    Marine Biochemical Sciences Group, Chemical Sciences Division, Hollings Marine Laboratory, National Institute of Standards and Technology, Charleston SC, USA.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Hollings Marine Laboratory, Marine Biochemical Sciences Group, National Institute of Standards and Technology, Charleston SC, United States; Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta GA, United States.
    Zhou, Senlin
    Department of Chemistry and Biochemistry, Wayne State University, Detroit MI, USA.
    Harmonizing Lipidomics: NIST Interlaboratory Comparison Exercise for Lipidomics using Standard Reference Material 1950 Metabolites in Frozen Human Plasma2017Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, nr 12, s. 2275-2288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 7.
    Castillo, S.
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, I.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Miettinen, J.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Data analysis tool for comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry2011Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, nr 8, s. 3058-3067Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 8.
    Dickens, Alex Mountfort
    et al.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland .
    Posti, Jussi P.
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland .
    Takala, Riikka Sk.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland .
    Ala-Seppälä, Henna Maria
    Department of Neurology,University of Turku, Turku, Finland .
    Mattila, Ismo
    Steno Diabetes Center AS, Gentofte, Denmark.
    Coles, Jonathan Coles
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Frantzén, Janek
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery,Turku University Hospital, Turku, Finland .
    Hutchinson, Peter John
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Katila, Ari J.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
    Kyllönen, Anna
    Department of Neurology, University of Turku, Turku, Finland .
    Maanpää, Henna-Riikka
    Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland.
    Newcombe, Virginia
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Norther Ireland.
    Outtrim, Joanne
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Tallus, Jussi
    Division of Anaesthesia, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Carpenter, Keri
    Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Menon, David
    Head, Division of Anaesthesia, Addenbrooke's Hospital, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Tenovuo, Olli
    Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland .
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury2018Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, nr 22, s. 2673-2683Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 9.
    Djekic, Demir
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Cardiology.
    Pinto, Rui
    Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
    Repsilber, Dirk
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Henein, Michael
    Department of Public Health and Clinical Medicine, Umeå University and Heart Centre, Umeå, Sweden; Molecular and Clinic Research Institute, St George University, London, UK; Institute of Environment, Health and Physical Sciences, Brunel University, London, UK.
    Serum untargeted lipidomic profiling reveals dysfunction of phospholipid metabolism in subclinical coronary artery disease2019Inngår i: Vascular Health and Risk Management, ISSN 1176-6344, E-ISSN 1178-2048, Vol. 15, s. 123-135Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Disturbed metabolism of cholesterol and triacylglycerols (TGs) carries increased risk for coronary artery calcification (CAC). However, the exact relationship between individual lipid species and CAC remains unclear. The aim of this study was to identify disturbances in lipid profiles involved in the calcification process, in an attempt to propose potential biomarker candidates.

    Patients and methods: We studied 70 patients at intermediate risk for coronary artery disease who had undergone coronary calcification assessment using computed tomography and Agatston coronary artery calcium score (CACS). Patients were divided into three groups: with no coronary calcification (NCC; CACS: 0; n=26), mild coronary calcification (MCC; CACS: 1-250; n=27), or severe coronary calcification (SCC; CACS: >250; n=17). Patients' serum samples were analyzed using liquid chromatography-mass spectrometry in an untargeted lipidomics approach.

    Results: We identified 103 lipids within the glycerolipid, glycerophospholipid, sphingolipid, and sterol lipid classes. After false discovery rate correction, phosphatidylcholine (PC)(16:0/20:4) in higher levels and PC(18:2/18:2), PC(36:3), and phosphatidylethanolamine(20:0/18:2) in lower levels were identified as correlates with SCC compared to NCC. There were no significant differences in the levels of individual TGs between the three groups; however, clustering the lipid profiles showed a trend for higher levels of saturated and monounsaturated TGs in SCC compared to NCC. There was also a trend for lower TG (49:2), TG(51:1), TG(54:5), and TG(56:8) levels in SCC compared to MCC.

    Conclusion: In this study we investigated the lipidome of patients with coronary calcification. Our results suggest that the calcification process may be associated with dysfunction in autophagy. The lipidomic biomarkers revealed in this study may aid in better assessment of patients with subclinical coronary artery disease.

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

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

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

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

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

  • 11.
    Frank, Elisabeth
    et al.
    Biomax Informatics AB, Planegg, Germany.
    Maier, Dieter
    Biomax Informatics AB, Planegg, Germany.
    Pajula, Juha
    VTT Technical Research Centre of Finland Ltd., Tampere, Finland.
    Suvitaival, Tommi
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Borgan, Faith
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Butz-Ostendorf, Markus
    Biomax Informatics AB, Planegg, Germany.
    Fischer, Alexander
    Philips GmbH Innovative Technologies, Aachen, Germany.
    Hietala, Jarmo
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Howes, Oliver
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Chemistry, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Janssen, Joost
    Child and Adolescent Psychiatry Department, School of Medicine, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
    Laurikainen, Heikki
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Moreno, Carmen
    Child and Adolescent Psychiatry Department, School of Medicine, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Investigación Sanitaria del Hospital Gregorio Marañón (IISGM), Madrid, Spain.
    Suvisaari, Jaana
    National Institute for Health and Welfare (THL), Helsinki, Finland.
    Van Gils, Mark
    VTT Technical Research Centre of Finland Ltd.,Tampere, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Platform for systems medicine research and diagnostic applications in psychotic disorders - The METSY project2018Inngår i: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 50, s. 40-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 12.
    Geng, Dawei
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Musse, Ayan Au
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Wigh, Viktoria
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Carlsson, Cecilia
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Engwall, Magnus
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Scherbak, Nikolai
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo2019Inngår i: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 170, s. 691-698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 13.
    Greiner, Thomas U.
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    The gut microbiota modulates glycaemic control and serum metabolite profiles in non-obese diabetic mice2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikkel-id e110359Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 14.
    Grip, Tove
    et al.
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Dyrlund, Thomas S.
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Ahonen, Linda
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Domellöf, Magnus
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Hernell, Olle
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Chemistry.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Institute, Helsinki, Finland.
    Lönnerdal, Bo
    Department of Nutrition, University of California, Davis, United States.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Academy University, Turku, Finland.
    Timby, Niklas
    Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden.
    Serum, plasma and erythrocyte membrane lipidomes in infants fed formula supplemented with bovine milk fat globule membranes2018Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 84, nr 5, s. 726-732Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 15.
    Götz, Alexandra
    et al.
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tyynismaa, Henna
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Euro, Liliya
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Ellonen, Pekka
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ojala, Tiina
    Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Hämäläinen, Riikka H
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tommiska, Johanna
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g.
    Raivio, Taneli
    Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Karikoski, Riitta
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tammela, Outi
    Pediatric Research Centre, Tampere University Hospital, Tampere, Finland.
    Simola, Kalle O J
    Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Paetau, Anders
    Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland.
    Tyni, Tiina
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Suomalainen, Anu
    Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy2011Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, nr 5, s. 635-642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 16.
    Hartonen, Minna
    et al.
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Ruskeepää, Anna-Liisa
    VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Helsiniki, Finland.
    Characterization of cerebrospinal fluid by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry2013Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1293, s. 142-149, artikkel-id S0021-9673(13)00567-0Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 17.
    Havula, Essi
    et al.
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Teesalu, Mari
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppälä, Heini
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Hasygar, Kiran
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Auvinen, Petri
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Sandmann, Thomas
    German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Hietakangas, Ville
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland; Department of Biosciences, University of Helsinki, Helsinki, Finland.
    Mondo/ChREBP-Mlx-regulated transcriptional network is essential for dietary sugar tolerance in Drosophila2013Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 4, artikkel-id e1003438Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 18.
    Helle, Anne
    et al.
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Hirsjärvi, Samuli
    Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Peltonen, Leena
    Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Hirvonen, Jouni
    Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Wiedmer, Susanne K.
    Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Quantitative Biology and Bioinformatics, VTT Technical Research Centre of Finland, Espoo, Finland.
    Novel, dynamic on-line analytical separation system for dissolution of drugs from poly(lactic acid) nanoparticles2010Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 51, nr 1, s. 125-130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel method for investigating drug release in a dynamic manner from nanoparticles including, but not limited to, biodegradable poly(lactic acid) (PLA) is reported. The PLA nanoparticles were prepared by the nanoprecipitation method. Two poorly soluble drugs, beclomethasone dipropionate (BDP) and indomethacin, were encapsulated into PLA nanoparticles, and their dissolution from the nanoparticles were followed in a dynamic way. The on-line method comprised a short column (vessel) packed with the PLA nanoparticles, on-line connected to an analytical liquid chromatographic column via a multiport switching valve equipped with two loops. The system allowed monitoring of the drug release profiles in real time, and the conditions for the drug release could be precisely controlled and easily changed. The effects of solvent composition and temperature on the rate of dissolution of the drugs from the PLA nanoparticles were investigated. The system proved to be linear for the drugs tested over the concentration range 10-3000 ng (n = 6, R(2) = 0.999 and 0.997 for indomethacin and beclomethasone, respectively) and repeatable (RSD of peak areas <0.5%). The recoveries of the dissolution study were quantitative (120 and 103% for indomethacin and beclomethasone, respectively).

  • 19.
    Hernández-Alvarez, María Isabel
    et al.
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Sebastián, David
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Vives, Sara
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Ivanova, Saška
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Bartoccioni, Paola
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Kakimoto, Pamela
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
    Plana, Natalia
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Veiga, Sónia R.
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
    Hernández, Vanessa
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Vasconcelos, Nuno
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Peddinti, Gopal
    VTT Technical Research Center of Finland, Espoo, Finland.
    Adrover, Anna
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Jové, Mariona
    Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
    Pamplona, Reinald
    Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
    Gordaliza-Alaguero, Isabel
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Calvo, Enrique
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Cabré, Noemí
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
    Castro, Rui
    Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
    Kuzmanic, Antonija
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Boutant, Marie
    Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
    Sala, David
    Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Fort, Joana
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Errasti-Murugarren, Ekaitz
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Rodrígues, Cecilia M. P.
    Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
    Orozco, Modesto
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
    Joven, Jorge
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
    Cantó, Carles
    Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
    Palacin, Manuel
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
    Fernández-Veledo, Sonia
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
    Vendrell, Joan
    Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Universitat Rovira i Virgili, Tarragona, Spain.
    Zorzano, Antonio
    Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease2019Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, nr 4, s. 881-895.e17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 20.
    Hilvo, Mika
    et al.
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Denkert, Carsten
    Institute of Pathology, Berlin, Germany.
    Lehtinen, Laura
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Müller, Berit
    Institute of Pathology, Berlin, Germany.
    Brockmöller, Scarlet
    Institute of Pathology, Berlin, Germany.
    Seppänen-Laakso, Tuulikki
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Budczies, Jan
    Institute of Pathology, Berlin, Germany.
    Bucher, Elmar
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Yetukuri, Laxman
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Castillo, Sandra
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Berg, Emilia
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Nygren, Heli
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Sysi-Aho, Marko
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Fiehn, Oliver
    Genome Center, University of California, Davis CA, United States.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Richter-Ehrenstein, Christiane
    cBreast Cancer Center, Charité University Hospital, Berlin, Germany.
    Radke, Cornelia
    Institute of Pathology, DRK Klinikum Berlin Köpenick, Berlin, Germany.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Iljin, Kristiina
    Bio and Process Technology, VTT Technical Research Centre of Finland, Turku, Finland.
    Oresic, Matej
    Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland.
    Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression2011Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, nr 9, s. 3236-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 21.
    Hilvo, Mika
    et al.
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Gade, Stephan
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Nekljudova, Valentina
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Seppänen-Laakso, Tuulikki
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Sysi-Aho, Marko
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Untch, Michael
    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
    Huober, Jens
    Department of Gynecology, University of Ulm, Ulm, Germany.
    von Minckwitz, Gunter
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Denkert, Carsten
    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland Espoo, Espoo, Finland.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients2014Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, nr 7, s. 1725-1733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 22.
    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 activity2015Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 80, nr 3, s. 473-479Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23.
    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 universitet, Institutionen för naturvetenskap och teknik. 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 universitet, Institutionen för medicinska vetenskaper. 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 obesity2014Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 1, s. 312-322Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 24.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Analytical methodologies utilized in the search for chronic disease biomarkers2010Inngår i: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 2, nr 5, s. 919-923Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Novel methodologies in metabolic profiling with a focus on molecular diagnostic applications2012Inngår i: Expert Review of Molecular Diagnostics, ISSN 1473-7159, E-ISSN 1744-8352, Vol. 12, nr 5, s. 527-538Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The metabolome contains all the biological end points of genomic, transcriptomic and proteomic perturbations, also including the influence of gut microbiota and the environment, giving a direct picture of an organism's ongoing metabolic state. Metabolomics thus has the potential to be an effective tool for early diagnosis of disease, and also to be a predictor of treatment response and survival. In recent years, the development of instrumental systems has enabled more comprehensive coverage of the metabolome. Advances in mass spectrometry and chromatography have particularly improved both the efficiency of nontargeted metabolic profiling as well as the sensitivity and reliability of targeted analyses. Mass spectrometric techniques are also increasingly becoming accepted as a routine diagnostic tool in clinical laboratories. This review summarizes the most recent advances and current challenges in metabolomics, with a focus on mass spectrometric methods utilized in biomarker research, highlighted with selected examples.

  • 26.
    Hyötyläinen, Tuulia
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik. 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 considerations2017Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1862, nr 8, s. 800-803Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 27.
    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 research2013Inngår i: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 57, nr 8, s. 1306-1318Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 28.
    Hyötyläinen, Tuulia
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik. 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 disease2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikkel-id 8994Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 29.
    Hyötyläinen, Tuulia
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik. 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 universitet, Institutionen för medicinska vetenskaper. 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 resistance2012Inngår i: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 8, nr 10, s. 2559-2565Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 30.
    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 considerations2015Inngår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 407, nr 17, s. 4973-4993, artikkel-id 8633Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 31.
    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 disease2014Inngår i: Progress in lipid research, ISSN 0163-7827, E-ISSN 1873-2194, Vol. 55, nr 1, s. 43-60Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 32.
    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 Research2015Inngår i: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 26, nr 12, s. 671-673Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 33.
    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 lipidomics2016Inngår i: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 8, nr 4, s. 351-364Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 34.
    Jäntti, Sirkku E.
    et al.
    VTT Technical Research Center of Finland, Espoo, Finland; Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Hartonen, Minna
    VTT Technical Research Center of Finland, Espoo, Finland.
    Hilvo, Mika
    VTT Technical Research Center of Finland, Espoo, Finland.
    Nygren, Heli
    VTT Technical Research Center of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Center of Finland, Espoo, Finland.
    Ketola, Raimo A.
    Department of Forensic Medicine, Hjelt Institute, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Kostiainen, Risto
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Steroid and steroid glucuronide profiles in urine during pregnancy determined by liquid chromatography-electrospray ionization-tandem mass spectrometry2013Inngår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 802, s. 56-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-MS/MS) method was developed for the analysis of steroids and their glucuronides in urine samples. The method provides high sensitivity and fast analysis, as both steroids and their glucuronides can be analyzed directly without hydrolysis or complex sample preparation. The method was applied in profiling of targeted and nontargeted steroids and steroid glucuronides during pregnancy. The concentrations of 11 of 27 targeted steroids and steroid glucuronides and the concentrations of 25 nontargeted steroid glucuronides increased about 10-400 fold during the pregnancy. The concentrations of most of these 36 compounds began to increase in the first days of the pregnancy, increased gradually during the pregnancy, achieved a maximum in late pregnancy, and decreased sharply after delivery. Exceptionally, the concentrations of allopregnanolone and 17-hydroxypregnenolone started to increase later than those of the other steroids. Moreover, the concentrations of E2 glucuronides began to decrease one week before the delivery, in contrast to most of the steroids and steroid glucuronides, whose concentrations dropped sharply during the delivery. Concentrations of 34 compounds decreased noticeably when the subject was on sick leave owing a series of painful contractions. The results suggest that steroids and especially steroid glucuronides may provide a valuable diagnostic tool to follow the course of pregnancy.

  • 35.
    Jäntti, Sirkku E.
    et al.
    VTT Technical Research Center of Finland, Espoo, Finland; Finnish Food Safety Authority Evira, Helsinki, Finland.
    Kivilompolo, Maarit
    VTT Technical Research Center of Finland, Espoo, Finland.
    Öhrnberg, Leena
    VTT Technical Research Center of Finland, Espoo, Finland.
    Pietiläinen, Kirsi H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland; FIMM, Institute for Molecular Medicine University of Helsinki, Helsinki, Finland.
    Nygren, Heli
    VTT Technical Research Center of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Steno Diabetes Center, Gentofte, Denmark.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Steno Diabetes Center, Gentofte, Denmark.
    Quantitative profiling of bile acids in blood, adipose tissue, intestine, and gall bladder samples using ultra high performance liquid chromatography-tandem mass spectrometry2014Inngår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 406, nr 30, s. 7799-7815Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An ultra high performance liquid chromatography tandem mass spectrometry method (UHPLC-MS/MS) was developed for the determination of 33 target and 28 unknown bile acids (BAs) in biological samples. Sixty-one BAs could be measured in 20 min using only a small amount of sample and with a simple sample preparation. The method proved to be very sensitive (limit of detection 5-350 pg/mL, lower limit of quantitation 0.1-2.6 ng/mL), linear (R(2) > 0.99) and reproducible (typically CV <15 % in biological matrixes). The method was used to analyze human adipose tissue, plasma, and serum (from same subjects) and mouse serum, gall bladder, small intestine, and colon samples (from same animals). Cholic acid, ursodeoxycholic acid, and chenodeoxycholic acid, deoxycholic acid, and their conjugates (mainly glycine, but also taurine conjugates) were the main metabolites in human samples, and cholic acid, glycine cholic acid, and several taurine conjugates in mouse samples. Using the method, 28 unknown BAs could also be detected. UHPLC-MS/MS spectra, accurate mass, and tissue distribution suggested that nine of the unknown bile acids were taurine conjugates, 13 were glycine conjugates, and six were intact BAs, respectively. To our knowledge, this was the first time BAs were detected in adipose tissue. Results showed that 17 targeted BAs were found at ng/g level in human adipose tissue. Our findings give a novel insight of the endogenous role of BAs in adipose tissue and their role as biomarkers (e.g., in metabolic diseases).

  • 36.
    Jørgenrud, Benedicte
    et al.
    Hormone Laboratory, Oslo University Hospital, Oslo, Norway; Hormone Laboratory, Aker Hospital, Oslo, Norway; Division of Women and Children's Health, Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
    Jalanko, Mikko
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Heliö, Tiina
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Jääskeläinen, Pertti
    Heart Center, Kuopio University Hospital, Kuopio, Finland.
    Laine, Mika
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Nieminen, Markku S
    Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
    Laakso, Markku
    Department of Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Kuusisto, Johanna
    University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
    The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 8, artikkel-id e0134184Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters.

    METHODS AND RESULTS: 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation.

    CONCLUSIONS: Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

  • 37.
    Jørgenrud, Benedicte
    et al.
    Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
    Jäntti, Sirkku
    Finnish Food Safety Authority Evira, Helsinki, Finland.
    Mattila, Ismo
    Steno Diabetes Center, Gentofte, Denmark.
    Pöhö, Päivi
    Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Rønningen, Kjersti S.
    Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.
    Yki-Järvinen, Hannele
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Steno Diabetes Center, Gentofte, Denmark.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Steno Diabetes Center, Gentofte, Denmark.
    The influence of sample collection methodology and sample preprocessing on the blood metabolic profile.2015Inngår i: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 7, nr 8, s. 991-1006Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: Blood serum and plasma have intrinsic differences in their composition and the preprocessing, such as clotting temperature in serum, and storage at room temperature may have further effect on metabolite concentrations.

    METHODS: The influence of sampling preprocessing on the metabolic profiles in serum and different types of plasma was investigated using liquid chromatography and comprehensive 2D gas chromatography coupled to a mass spectrometer.

    RESULTS: The profiles of polar metabolites were significantly dependent on the type of the sample, while lipid profiles were similar in serum and different types of plasma. Extended storage of plasma at room temperature resulted in degradation of lipids already after 1 day. Serum clotting at room temperature generally resulted in higher metabolite concentration compared with serum clotting on ice.

  • 38.
    Jørgenrud, Benedicte
    et al.
    Department of Pediatric Research, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway; Hormone Laboratory, Department of Medical Biochemistry, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.
    Stene, Lars C
    Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
    Tapia, German
    Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
    Bøås, Håkon
    Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
    Pepaj, Milaim
    Hormone Laboratory, Department of Medical Biochemistry, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.
    Berg, Jens P
    Division of Diagnostic and Intervention, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.
    Thorsby, Per M
    Hormone Laboratory, Department of Medical Biochemistry, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.
    Orešič, Matej
    Systems Medicine Department, Steno Diabetes Centre, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Systems Medicine Department, Steno Diabetes Centre, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Rønningen, Kjersti S
    Department of Pediatric Research, Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.
    Longitudinal plasma metabolic profiles, infant feeding, and islet autoimmunity in the MIDIA study2017Inngår i: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 18, nr 2, s. 111-119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: The aim of this study was to investigate the longitudinal plasma metabolic profiles in healthy infants and the potential association with breastfeeding duration and islet autoantibodies predictive of type 1 diabetes.

    METHOD: Up to four longitudinal plasma samples from age 3 months from case children who developed islet autoimmunity (n = 29) and autoantibody-negative control children (n = 29) with the HLA DR4-DQ8/DR3-DQ2 genotype were analyzed using two-dimensional gas chromatography coupled to a time-of-flight mass spectrometer for detection of small polar metabolites.

    RESULTS: Plasma metabolite levels were found to depend strongly on age, with fold changes varying up to 50% from age 3 to 24 months (p < 0.001 after correction for multiple testing). Tyrosine levels tended to be lower in case children, but this was not significant after correction for multiple testing. Ornithine levels were lower in case children compared with the controls at the time of seroconversion, but the difference was not statistically significant after correcting for multiple testing. Breastfeeding for at least 3 months as compared with shorter duration was associated with higher plasma levels of isoleucine, and lower levels of methionine and 3,4-dihydroxybutyric acid at 3 months of age.

    CONCLUSIONS: Plasma levels of several small, polar metabolites changed with age during early childhood, independent of later islet autoimmunity status and sex. Breastfeeding was associated with higher levels of branched-chain amino acids, and lower levels of methionine and 3,4-dihydroxybutyric acid.

  • 39.
    Ketola, Kirsi
    et al.
    Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland; University of Turku, Turku, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Vuoristo, Anu
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Ruskeepää, Anna Liisa
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli Pekka
    Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland; University of Turku, Turku, Finland; Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland.
    Iljin, Kristiina
    Medical Biotechnology, VTT Technical Research Centre of Finland, Espoo, Finland; University of Turku, Turku, Finland.
    Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress2012Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, nr 1, s. 99-106Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: We have shown that a sodium ionophore monensin inhibits prostate cancer cell growth. A structurally related compound to monensin, salinomycin, was recently identified as a putative cancer stem cell inhibitor.

    METHODS: The growth inhibitory potential of salinomycin was studied in a panel of prostate cells. To get insights into the mechanism of action, a variety of assays such as gene expression and steroid profiling were performed in salinomycin-exposed prostate cancer cells.

    RESULTS: Salinomycin inhibited the growth of prostate cancer cells, but did not affect non-malignant prostate epithelial cells. Salinomycin impacted on prostate cancer stem cell functions as evidenced by reduced aldehyde dehydrogenase activity and the fraction of CD44(+) cells. Moreover, salinomycin reduced the expression of MYC, AR and ERG, induced oxidative stress as well as inhibited nuclear factor-κB activity and cell migration. Furthermore, profiling steroid metabolites revealed increased levels of oxidative stress-inducing steroids 7-ketocholesterol and aldosterone and decreased levels of antioxidative steroids progesterone and pregnenolone in salinomycin-exposed prostate cancer cells.

    CONCLUSION: Our results indicate that salinomycin inhibits prostate cancer cell growth and migration by reducing the expression of key prostate cancer oncogenes, inducing oxidative stress, decreasing the antioxidative capacity and cancer stem cell fraction.

  • 40.
    Kivilompolo, Marit
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Öhrnberg, Leena
    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.
    Rapid quantitative analysis of carnitine and acylcarnitines by ultra-high performance-hydrophilic interaction liquid chromatography-tandem mass spectrometry2013Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1292, s. 189-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    L-Carnitine and its acyl esters (acylcarnitines) play an important role in the metabolism of fatty acids. However, most of the present methods for the quantitative analysis of acylcarnitines have restrictions both in sample preparation and in chromatographic separation. Herein we present a validated method for determination of carnitine and eleven acylcarnitines in human serum and rat tissue biopsies by using ultra-high performance-hydrophilic interaction liquid chromatography-tandem mass spectrometry (UHP-HILIC-MS/MS). The procedure uses minimal sample preparation including only addition of organic solvent, labeled internal standard, incubation and centrifugation. The separation is performed without derivatization or addition of ion-pairing reagent within 7 min on a hydrophilic interaction liquid chromatographic column with mass spectrometric detection. The method is linear in response over the concentration range from 20 to 600 ng/ml for carnitine and acetylcarnitine and 5-200 ng/ml for the other acylcarnitines, with correlation coefficients higher than 0.994. Recoveries were higher than 88% for most of the compounds. Limits of detection were 5 ng/ml for carnitine and acetylcarnitine and approximately 0.5 ng/ml for other acylcarnitines. The method was applied to the analysis of serum and tissue samples.

  • 41.
    Kostic, Aleksandar D.
    et al.
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Center for Computational and Integrative Bioogy, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Department of Biostatistics, Harvard School of Public Health, Boston MA, United States.
    Gevers, Dirk
    Broad Institute of MIT and Harvard, Cambridge MA, United States.
    Siljander, Heli
    Department of Biostatistics, Harvard School of Public Health, Boston MA, United States; Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
    Vatanen, Tommi
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Department of Information and Computer Science, Aalto University School of Science, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Hämäläinen, Anu-Maaria
    Department of Pediatrics, Jorvi Hospital, Espoo, Finland.
    Peet, Aleksandr
    Department of Pediatrics, University of Tartu, Estonia and Tartu University Hospital, Tartu, Estonia.
    Tillmann, Vallo
    Department of Pediatrics, University of Tartu, Estonia and Tartu University Hospital, Tartu, Estonia.
    Pöhö, Päivi
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    Steno Diabetes Center, Gentofte, Denmark; VTT Technical Research Centre of Finland, Espoo, Finland.
    Lähdesmäki, Harri
    Franzosa, Eric A.
    Department of Biostatistics, Harvard School of Public Health, Boston MA, United States.
    Vaarala, Outi
    Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    de Goffau, Marcus
    Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Harmsen, Hermie
    Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Ilonen, Jorma
    Immunogenetics Laboratory, University of Turku, Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
    Virtanen, Suvi M.
    Department of Lifestyle and Participation, National Institute for Health and Welfare, Helsinki, Finland; School of Health Sciences, University of Tampere, Tampere, Finland; Science Centre, Pirkanmaa Hospital District, Tampere, Finland.
    Clish, Clary B.
    Broad Institute of MIT and Harvard, Cambridge MA, United States.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Broad Institute of MIT and Harvard, Cambridge MA, United States; VTT Technical Research Centre of Finland, Espoo, Finland.
    Huttenhower, Curtis
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Department of Biostatistics, Harvard School of Public Health, Boston MA, United States.
    Knip, Mikael
    Children's Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Xavier, Ramnik J.
    Broad Institute of MIT and Harvard, Cambridge MA, United States; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge MA, United States.
    The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes2015Inngår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 17, nr 2, s. 260-273, artikkel-id S1931-3128(15)00021-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.

  • 42.
    Kurko, Johanna
    et al.
    Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
    Tringham, Maaria
    Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
    Tanner, Laura
    Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland; Department of Clinical Genetics, Turku University Hospital, Turku, Finland.
    Näntö-Salonen, Kirsti
    Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
    Vähä-Mäkilä, Mari
    Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Pöhö, Päivi
    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Lietzen, Niina
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Mattila, Ismo
    Steno Diabetes Center A/S, Gentofte, Denmark.
    Olkku, Anu
    Eastern Finland Laboratory Centre, Kuopio, Finland.
    Hyötyläinen, Tuulia
    Steno Diabetes Center A/S, Gentofte, Denmark.
    Orešič, Matej
    Steno Diabetes Center A/S, Gentofte, Denmark.
    Simell, Olli
    Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
    Niinikoski, Harri
    Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
    Mykkänen, Juha
    Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
    Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)2016Inngår i: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 65, nr 9, s. 1361-1375Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Lysinuric protein intolerance (LPI [MIM 222700]) is an aminoaciduria with defective transport of cationic amino acids in epithelial cells in the small intestine and proximal kidney tubules due to mutations in the SLC7A7 gene. LPI is characterized by protein malnutrition, failure to thrive and hyperammonemia. Many patients also suffer from combined hyperlipidemia and chronic kidney disease (CKD) with an unknown etiology.

    METHODS: Here, we studied the plasma metabolomes of the Finnish LPI patients (n=26) and healthy control individuals (n=19) using a targeted platform for analysis of amino acids as well as two analytical platforms with comprehensive coverage of molecular lipids and polar metabolites.

    RESULTS: Our results demonstrated that LPI patients have a dichotomy of amino acid profiles, with both decreased essential and increased non-essential amino acids. Altered levels of metabolites participating in pathways such as sugar, energy, amino acid and lipid metabolism were observed. Furthermore, of these metabolites, myo-inositol, threonic acid, 2,5-furandicarboxylic acid, galactaric acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid and beta-aminoisobutyric acid associated significantly (P<0.001) with the CKD status. Lipid analysis showed reduced levels of phosphatidylcholines and elevated levels of triacylglycerols, of which long-chain triacylglycerols associated (P<0.01) with CKD.

    CONCLUSIONS: This study revealed an amino acid imbalance affecting the basic cellular metabolism, disturbances in plasma lipid composition suggesting hepatic steatosis and fibrosis and novel metabolites correlating with CKD in LPI. In addition, the CKD-associated metabolite profile along with increased nitrite plasma levels suggests that LPI may be characterized by increased oxidative stress and apoptosis, altered microbial metabolism in the intestine and uremic toxicity.

  • 43.
    La Torre, Daria
    et al.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Larsson, Helena E.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Ivarsson, Sten A.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Lernmark, Åke
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes2013Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 11, s. 3951-3956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. This study used metabolomics to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before 8 years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before 8 years of age and 76 healthy control subjects matched for HLA risk, sex, and date of birth, as well as the mother's age and gestational age, revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before 4 years of age. Reduced levels of triglycerides correlated to gestational age in index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord-blood total lysophosphatidylcholines in index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute to early induction of islet autoimmunity.

  • 44.
    Lamichhane, Santosh
    et al.
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Ahonen, Linda
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Dyrlund, Thomas Sparholt
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Dickens, Alex M
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Siljander, Heli
    Children's Hospital, University of Helsinki, Helsinki University Hospital and Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    Hyöty, Heikki
    Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
    Veijola, Riitta
    Department of Pediatrics, PEDEGO Research Unit, Medical Research Centre, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Knip, Mikael
    Children's Hospital, University of Helsinki, Helsinki University Hospital and Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes2019Inngår i: Biomolecules, E-ISSN 2218-273X, Vol. 9, nr 1, artikkel-id E33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.

  • 45.
    Lamichhane, Santosh
    et al.
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Ahonen, Linda
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Dyrlund, Thomas Sparholt
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Kemppainen, Esko
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Siljander, Heli
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    Hyöty, Heikki
    Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
    Veijola, Riitta
    Department of Paediatrics, PEDEGO Research Unit, University of Oulu Finland, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Dynamics of Plasma Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes - Type 1 Diabetes Prediction and Prevention Study (DIPP)2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 10635Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched controls (CTR). Sphingomyelins were found to be persistently downregulated in PT1D when compared to the P1Ab and CTR groups. Triacylglycerols and phosphatidylcholines were mainly downregulated in PT1D as compared to P1Ab at the age of 3 months. Our study suggests that distinct lipidomic signatures characterize children who progressed to islet autoimmunity or overt T1D, which may be helpful in the identification of at-risk children before the initiation of autoimmunity.

  • 46.
    Lamichhane, Santosh
    et al.
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Ahonen, Linda
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Dyrlund, Thomas Sparholt
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Siljander, Heli
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    Hyöty, Heikki
    Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
    Veijola, Riitta
    Department of Paediatrics, PEDEGO Research Unit, Medical Research Centre, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Chemistry.
    Knip, Mikael
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    A longitudinal plasma lipidomics dataset from children who developed islet autoimmunity and type 1 diabetes2018Inngår i: Scientific Data, E-ISSN 2052-4463, Vol. 5, artikkel-id 180250Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early prediction and prevention of type 1 diabetes (T1D) are currently unmet medical needs. Previous metabolomics studies suggest that children who develop T1D are characterised by a distinct metabolic profile already detectable during infancy, prior to the onset of islet autoimmunity. However, the specificity of persistent metabolic disturbances in relation T1D development has not yet been established. Here, we report a longitudinal plasma lipidomics dataset from (1) 40 children who progressed to T1D during follow-up, (2) 40 children who developed single islet autoantibody but did not develop T1D and (3) 40 matched controls (6 time points: 3, 6, 12, 18, 24 and 36 months of age). This dataset may help other researchers in studying age-dependent progression of islet autoimmunity and T1D as well as of the age-dependence of lipidomic profiles in general. Alternatively, this dataset could more broadly used for the development of methods for the analysis of longitudinal multivariate data.

  • 47.
    Lamichhane, Santosh
    et al.
    Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
    Kemppainen, Esko
    Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
    Trošt, Kajetan
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Siljander, Heli
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, University of Helsinki, Helsinki, Finland.
    Hyöty, Heikki
    Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
    Veijola, Riitta
    Department of Pediatrics, PEDEGO Research Unit, Medical Research Centre, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Knip, Mikael
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, University of Helsinki, Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland; .
    Circulating metabolites in progression to islet autoimmunity and type 1 diabetes2019Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS/HYPOTHESIS: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.

    METHODS: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.

    RESULTS: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.

    CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

  • 48.
    Lamichhane, Santosh
    et al.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Sen, Partho
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Dickens, Alex M.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Orešič, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    An Overview of Metabolomics Data Analysis: Current Tools and Future Perspectives2018Inngår i: Data Analysis for Omic Sciences: Methods and Applications / [ed] Joaquim Jaumot; Carmen Bedia; Romà Tauler, Elsevier, 2018, Vol. 82, s. 387-413Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Metabolomics is a study of small molecules in the body and the associated metabolic pathways and is considered to provide a close link between organism's genotype and phenotype. As with other ‘omics’ techniques, metabolomic analysis generates large-scale and complex datasets. Therefore, various data analysis tools are needed to extract biologically relevant information. The data analysis workflows in metabolomics studies are generally complex and involve several steps. In this chapter, we highlight the concept of metabolomics workflow and discuss the data analysis strategies for metabolomics experiments. We also discuss the available tools that can assist in biological interpretation of metabolomics data. We also present an emerging approach of developing genome-scale metabolic models to study cellular metabolism.

  • 49.
    Lankinen, Maria
    et al.
    Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
    Schwab, Ursula
    Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Institute of Clinical Medicine, Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kolehmainen, Marjukka
    Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
    Paananen, Jussi
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Poutanen, Kaisa
    Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Risérus, Ulf
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Savolainen, Markku J.
    Research Center for Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
    Hukkanen, Janne
    Research Center for Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
    Brader, Lea
    Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Marklund, Matti
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Rosqvist, Fredrik
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.
    Hermansen, Kjeld
    Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Cloetens, Lieselotte
    Biomedical Nutrition, Pure and Applied Biochemistry, Lund University, Lund, Sweden.
    Önning, Gunilla
    Biomedical Nutrition, Pure and Applied Biochemistry, Lund University, Lund, Sweden.
    Thorsdottir, Inga
    Unit for Nutrition Research, Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, , Reykjavik, Iceland; Landspitali – University Hospital, Reykjavik, Iceland.
    Gunnarsdottir, Ingibjorg
    Unit for Nutrition Research, Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, , Reykjavik, Iceland; Landspitali – University Hospital, Reykjavik, Iceland.
    Åkesson, Björn
    Biomedical Nutrition, Pure and Applied Biochemistry, Lund University, Lund, Sweden; Department of Clinical Nutrition, Skåne University Hospital, Lund, Sweden.
    Dragsted, Lars Ove
    Faculty of Science, Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, Denmark.
    Uusitupa, Matti
    Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Research Unit, Kuopio University Hospital, Kuopio, Finland; .
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    A Healthy Nordic Diet Alters the Plasma Lipidomic Profile in Adults with Features of Metabolic Syndrome in a Multicenter Randomized Dietary Intervention2016Inngår i: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 146, nr 4, s. 662-672Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known.

    OBJECTIVE: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome.

    METHODS: Men and women (n = 200) with features of metabolic syndrome [mean age: 55 y; body mass index (in kg/m(2)): 31.6] were randomly assigned to either a healthy Nordic (n = 104) or a control (n = 96) diet for 18 or 24 wk at 6 centers. Of the participants, 156 completed the study with plasma lipidomic measurements. The healthy Nordic diet consisted of whole grains, fruits, vegetables, berries, vegetable oils and margarines, fish, low-fat milk products, and low-fat meat. An average Nordic diet served as the control diet and included low-fiber cereal products, dairy fat-based spreads, regular-fat milk products, and a limited amount of fruits, vegetables, and berries. Lipidomic profiles were measured at baseline, week 12, and the end of the intervention (18 or 24 wk) by using ultraperformance liquid chromatography mass spectrometry. The effects of the diets on the lipid variables were analyzed with linear mixed-effects models. Data from centers with 18- or 24-wk duration were also analyzed separately.

    RESULTS: Changes in 21 plasma lipids differed significantly between the groups at week 12 (false discovery rate P < 0.05), including increases in plasmalogens and decreases in ceramides in the healthy Nordic diet group compared with the control group. At the end of the study, changes in lipidomic profiles did not differ between the groups. However, when the intervention lasted 24 wk, changes in 8 plasma lipids that had been identified at 12 wk, including plasmalogens, were sustained. There were no differences in changes in plasma lipids between groups with an intervention of 18 wk. By the dietary biomarker score, adherence to diet did not explain the difference in the results related to the duration of the study.

    CONCLUSIONS: A healthy Nordic diet transiently modified the plasma lipidomic profile, specifically by increasing the concentrations of antioxidative plasmalogens and decreasing insulin resistance-inducing ceramides. This trial was registered at clinicaltrials.gov as NCT00992641.

  • 50.
    Laurila, Pirkka-Pekka
    et al.
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
    Surakka, Ida
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Sarin, Antti-Pekka
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. VTT Technical Research Centre of Finland, Espoo, Finland.
    Söderlund, Sanni
    Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
    Naukkarinen, Jussi
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Tang, Jing
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kettunen, Johannes
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Mirel, Daniel B
    Program in Medical and Population Genetics, Broad Institute, Cambridge MA, United States.
    Soronen, Jarkko
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Lehtimäki, Terho
    Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland.
    Ruokonen, Aimo
    Institute of Diagnostics, University of Oulu, Oulu, Finland.
    Ehnholm, Christian
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Eriksson, Johan G.
    Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Vasa Central Hospital, Vasa, FinlandM; Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Salomaa, Veikko
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Jula, Antti
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Raitakari, Olli T
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Clinical Physiology, University of Turku, Turku University Hospital, Turku, Finland.
    Järvelin, Marjo-Riitta
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland.
    Palotie, Aarno
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom; Program in Medical and Population Genetics, Broad Institute, Cambridge MA, United States.
    Peltonen, Leena
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. VTT Technical Research Centre of Finland, Espoo, Finland.
    Jauhiainen, Matti
    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Taskinen, Marja-Riitta
    Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
    Ripatti, Samuli
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
    Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol2013Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 33, nr 4, s. 847-857Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450).

    APPROACH AND RESULTS: In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies-identified HDL genes.

    CONCLUSIONS: Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis-expression quantitative trait loci (cis-eQTL) variants in HLA region to be associated with low HDL-C.

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