Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.
Identifieur interne : 000622 ( Main/Exploration ); précédent : 000621; suivant : 000623Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.
Auteurs : Adil Mardinoglu [Suède] ; Elias Bjornson [Suède] ; Cheng Zhang [Suède] ; Martina Klevstig [Suède] ; Sanni Söderlund [Finlande] ; Marcus St Hlman [Suède] ; Martin Adiels [Suède] ; Antti Hakkarainen [Finlande] ; Nina Lundbom [Finlande] ; Murat Kilicarslan [Pays-Bas] ; Björn M. Hallström [Suède] ; Jesper Lundbom [Finlande] ; Bruno Vergès [France] ; Peter Hugh R. Barrett [Australie] ; Gerald F. Watts [Australie] ; Mireille J. Serlie [Pays-Bas] ; Jens Nielsen [Suède] ; Mathias Uhlén [Suède] ; Ulf Smith [Suède] ; Hanns-Ulrich Marschall [Suède] ; Marja-Riitta Taskinen [Finlande] ; Jan Boren [Suède]Source :
- Molecular systems biology [ 1744-4292 ] ; 2017.
Descripteurs français
- KwdFr :
- Adulte d'âge moyen, Animaux, Femelle, Foie (enzymologie), Foie (métabolisme), Glutathion (métabolisme), Glycine (sang), Génome, Humains, Lipoprotéines (métabolisme), Modèles animaux de maladie humaine, Modélisation spécifique au patient, Mâle, Métabolomique (), NAD (métabolisme), Régulation de l'expression des gènes codant pour des enzymes, Souris, Stéatose hépatique non alcoolique (diétothérapie), Stéatose hépatique non alcoolique (génétique), Stéatose hépatique non alcoolique (métabolisme), Sérine (administration et posologie), Sérine (sang), Sérine (usage thérapeutique).
- MESH :
- administration et posologie : Sérine.
- diétothérapie : Stéatose hépatique non alcoolique.
- enzymologie : Foie.
- génétique : Stéatose hépatique non alcoolique.
- métabolisme : Foie, Glutathion, Lipoprotéines, NAD, Stéatose hépatique non alcoolique.
- sang : Glycine, Sérine.
- usage thérapeutique : Sérine.
- Adulte d'âge moyen, Animaux, Femelle, Génome, Humains, Modèles animaux de maladie humaine, Modélisation spécifique au patient, Mâle, Métabolomique, Régulation de l'expression des gènes codant pour des enzymes, Souris.
English descriptors
- KwdEn :
- Animals, Disease Models, Animal, Female, Gene Expression Regulation, Enzymologic, Genome, Glutathione (metabolism), Glycine (blood), Humans, Lipoproteins (metabolism), Liver (enzymology), Liver (metabolism), Male, Metabolomics (methods), Mice, Middle Aged, NAD (metabolism), Non-alcoholic Fatty Liver Disease (diet therapy), Non-alcoholic Fatty Liver Disease (genetics), Non-alcoholic Fatty Liver Disease (metabolism), Patient-Specific Modeling, Serine (administration & dosage), Serine (blood), Serine (therapeutic use).
- MESH :
- chemical , administration & dosage : Serine.
- chemical , blood : Glycine, Serine.
- chemical , metabolism : Glutathione, Lipoproteins, NAD.
- diet therapy : Non-alcoholic Fatty Liver Disease.
- enzymology : Liver.
- genetics : Non-alcoholic Fatty Liver Disease.
- metabolism : Liver, Non-alcoholic Fatty Liver Disease.
- methods : Metabolomics.
- chemical , therapeutic use : Serine.
- Animals, Disease Models, Animal, Female, Gene Expression Regulation, Enzymologic, Genome, Humans, Male, Mice, Middle Aged, Patient-Specific Modeling.
Abstract
To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.
PubMed: 28254760
Affiliations:
- Australie, Finlande, France, Pays-Bas, Suède
- Bourgogne, Bourgogne-Franche-Comté, Hollande-Septentrionale, Svealand
- Amsterdam, Dijon, Stockholm
- Université d'Amsterdam
Links toward previous steps (curation, corpus...)
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- to stream PubMed, to step Checkpoint: 001010
- to stream Ncbi, to step Merge: 004396
- to stream Ncbi, to step Curation: 004396
- to stream Ncbi, to step Checkpoint: 004396
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- to stream Main, to step Curation: 000622
Le document en format XML
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Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Klevstig, Martina" sort="Klevstig, Martina" uniqKey="Klevstig M" first="Martina" last="Klevstig">Martina Klevstig</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Soderlund, Sanni" sort="Soderlund, Sanni" uniqKey="Soderlund S" first="Sanni" last="Söderlund">Sanni Söderlund</name><affiliation wicri:level="1"><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="St Hlman, Marcus" sort="St Hlman, Marcus" uniqKey="St Hlman M" first="Marcus" last="St Hlman">Marcus St Hlman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Adiels, Martin" sort="Adiels, Martin" uniqKey="Adiels M" first="Martin" last="Adiels">Martin Adiels</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Hakkarainen, Antti" sort="Hakkarainen, Antti" uniqKey="Hakkarainen A" first="Antti" last="Hakkarainen">Antti Hakkarainen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Lundbom, Nina" sort="Lundbom, Nina" uniqKey="Lundbom N" first="Nina" last="Lundbom">Nina Lundbom</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Kilicarslan, Murat" sort="Kilicarslan, Murat" uniqKey="Kilicarslan M" first="Murat" last="Kilicarslan">Murat Kilicarslan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region><settlement type="city">Amsterdam</settlement></placeName><orgName type="university">Université d'Amsterdam</orgName></affiliation></author><author><name sortKey="Hallstrom, Bjorn M" sort="Hallstrom, Bjorn M" uniqKey="Hallstrom B" first="Björn M" last="Hallström">Björn M. Hallström</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Lundbom, Jesper" sort="Lundbom, Jesper" uniqKey="Lundbom J" first="Jesper" last="Lundbom">Jesper Lundbom</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Verges, Bruno" sort="Verges, Bruno" uniqKey="Verges B" first="Bruno" last="Vergès">Bruno Vergès</name><affiliation wicri:level="3"><nlm:affiliation>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon</wicri:regionArea><placeName><region type="region">Bourgogne-Franche-Comté</region><region type="old region">Bourgogne</region><settlement type="city">Dijon</settlement></placeName></affiliation></author><author><name sortKey="Barrett, Peter Hugh R" sort="Barrett, Peter Hugh R" uniqKey="Barrett P" first="Peter Hugh R" last="Barrett">Peter Hugh R. Barrett</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA</wicri:regionArea><wicri:noRegion>WA</wicri:noRegion></affiliation></author><author><name sortKey="Watts, Gerald F" sort="Watts, Gerald F" uniqKey="Watts G" first="Gerald F" last="Watts">Gerald F. Watts</name><affiliation wicri:level="1"><nlm:affiliation>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA</wicri:regionArea><wicri:noRegion>WA</wicri:noRegion></affiliation></author><author><name sortKey="Serlie, Mireille J" sort="Serlie, Mireille J" uniqKey="Serlie M" first="Mireille J" last="Serlie">Mireille J. Serlie</name><affiliation wicri:level="4"><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region><settlement type="city">Amsterdam</settlement></placeName><orgName type="university">Université d'Amsterdam</orgName></affiliation></author><author><name sortKey="Nielsen, Jens" sort="Nielsen, Jens" uniqKey="Nielsen J" first="Jens" last="Nielsen">Jens Nielsen</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Uhlen, Mathias" sort="Uhlen, Mathias" uniqKey="Uhlen M" first="Mathias" last="Uhlén">Mathias Uhlén</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Smith, Ulf" sort="Smith, Ulf" uniqKey="Smith U" first="Ulf" last="Smith">Ulf Smith</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Marschall, Hanns Ulrich" sort="Marschall, Hanns Ulrich" uniqKey="Marschall H" first="Hanns-Ulrich" last="Marschall">Hanns-Ulrich Marschall</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Taskinen, Marja Riitta" sort="Taskinen, Marja Riitta" uniqKey="Taskinen M" first="Marja-Riitta" last="Taskinen">Marja-Riitta Taskinen</name><affiliation wicri:level="1"><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Boren, Jan" sort="Boren, Jan" uniqKey="Boren J" first="Jan" last="Boren">Jan Boren</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.</nlm:affiliation><country wicri:rule="url">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28254760</idno><idno type="pmid">28254760</idno><idno type="wicri:Area/PubMed/Corpus">001013</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001013</idno><idno type="wicri:Area/PubMed/Curation">001010</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001010</idno><idno type="wicri:Area/PubMed/Checkpoint">001010</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001010</idno><idno type="wicri:Area/Ncbi/Merge">004396</idno><idno type="wicri:Area/Ncbi/Curation">004396</idno><idno type="wicri:Area/Ncbi/Checkpoint">004396</idno><idno type="wicri:Area/Main/Merge">000617</idno><idno type="wicri:Area/Main/Curation">000622</idno><idno type="wicri:Area/Main/Exploration">000622</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.</title><author><name sortKey="Mardinoglu, Adil" sort="Mardinoglu, Adil" uniqKey="Mardinoglu A" first="Adil" last="Mardinoglu">Adil Mardinoglu</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.</nlm:affiliation><country wicri:rule="url">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Bjornson, Elias" sort="Bjornson, Elias" uniqKey="Bjornson E" first="Elias" last="Bjornson">Elias Bjornson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Cheng" sort="Zhang, Cheng" uniqKey="Zhang C" first="Cheng" last="Zhang">Cheng Zhang</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Klevstig, Martina" sort="Klevstig, Martina" uniqKey="Klevstig M" first="Martina" last="Klevstig">Martina Klevstig</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Soderlund, Sanni" sort="Soderlund, Sanni" uniqKey="Soderlund S" first="Sanni" last="Söderlund">Sanni Söderlund</name><affiliation wicri:level="1"><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="St Hlman, Marcus" sort="St Hlman, Marcus" uniqKey="St Hlman M" first="Marcus" last="St Hlman">Marcus St Hlman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Adiels, Martin" sort="Adiels, Martin" uniqKey="Adiels M" first="Martin" last="Adiels">Martin Adiels</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Hakkarainen, Antti" sort="Hakkarainen, Antti" uniqKey="Hakkarainen A" first="Antti" last="Hakkarainen">Antti Hakkarainen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Lundbom, Nina" sort="Lundbom, Nina" uniqKey="Lundbom N" first="Nina" last="Lundbom">Nina Lundbom</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Kilicarslan, Murat" sort="Kilicarslan, Murat" uniqKey="Kilicarslan M" first="Murat" last="Kilicarslan">Murat Kilicarslan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region><settlement type="city">Amsterdam</settlement></placeName><orgName type="university">Université d'Amsterdam</orgName></affiliation></author><author><name sortKey="Hallstrom, Bjorn M" sort="Hallstrom, Bjorn M" uniqKey="Hallstrom B" first="Björn M" last="Hallström">Björn M. Hallström</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Lundbom, Jesper" sort="Lundbom, Jesper" uniqKey="Lundbom J" first="Jesper" last="Lundbom">Jesper Lundbom</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Verges, Bruno" sort="Verges, Bruno" uniqKey="Verges B" first="Bruno" last="Vergès">Bruno Vergès</name><affiliation wicri:level="3"><nlm:affiliation>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon</wicri:regionArea><placeName><region type="region">Bourgogne-Franche-Comté</region><region type="old region">Bourgogne</region><settlement type="city">Dijon</settlement></placeName></affiliation></author><author><name sortKey="Barrett, Peter Hugh R" sort="Barrett, Peter Hugh R" uniqKey="Barrett P" first="Peter Hugh R" last="Barrett">Peter Hugh R. Barrett</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA</wicri:regionArea><wicri:noRegion>WA</wicri:noRegion></affiliation></author><author><name sortKey="Watts, Gerald F" sort="Watts, Gerald F" uniqKey="Watts G" first="Gerald F" last="Watts">Gerald F. Watts</name><affiliation wicri:level="1"><nlm:affiliation>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA</wicri:regionArea><wicri:noRegion>WA</wicri:noRegion></affiliation></author><author><name sortKey="Serlie, Mireille J" sort="Serlie, Mireille J" uniqKey="Serlie M" first="Mireille J" last="Serlie">Mireille J. Serlie</name><affiliation wicri:level="4"><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region><settlement type="city">Amsterdam</settlement></placeName><orgName type="university">Université d'Amsterdam</orgName></affiliation></author><author><name sortKey="Nielsen, Jens" sort="Nielsen, Jens" uniqKey="Nielsen J" first="Jens" last="Nielsen">Jens Nielsen</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Uhlen, Mathias" sort="Uhlen, Mathias" uniqKey="Uhlen M" first="Mathias" last="Uhlén">Mathias Uhlén</name><affiliation wicri:level="3"><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Smith, Ulf" sort="Smith, Ulf" uniqKey="Smith U" first="Ulf" last="Smith">Ulf Smith</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Marschall, Hanns Ulrich" sort="Marschall, Hanns Ulrich" uniqKey="Marschall H" first="Hanns-Ulrich" last="Marschall">Hanns-Ulrich Marschall</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author><author><name sortKey="Taskinen, Marja Riitta" sort="Taskinen, Marja Riitta" uniqKey="Taskinen M" first="Marja-Riitta" last="Taskinen">Marja-Riitta Taskinen</name><affiliation wicri:level="1"><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Boren, Jan" sort="Boren, Jan" uniqKey="Boren J" first="Jan" last="Boren">Jan Boren</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.</nlm:affiliation><country wicri:rule="url">Suède</country><wicri:regionArea>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg</wicri:regionArea><wicri:noRegion>Gothenburg</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular systems biology</title><idno type="eISSN">1744-4292</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Gene Expression Regulation, Enzymologic</term><term>Genome</term><term>Glutathione (metabolism)</term><term>Glycine (blood)</term><term>Humans</term><term>Lipoproteins (metabolism)</term><term>Liver (enzymology)</term><term>Liver (metabolism)</term><term>Male</term><term>Metabolomics (methods)</term><term>Mice</term><term>Middle Aged</term><term>NAD (metabolism)</term><term>Non-alcoholic Fatty Liver Disease (diet therapy)</term><term>Non-alcoholic Fatty Liver Disease (genetics)</term><term>Non-alcoholic Fatty Liver Disease (metabolism)</term><term>Patient-Specific Modeling</term><term>Serine (administration & dosage)</term><term>Serine (blood)</term><term>Serine (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte d'âge moyen</term><term>Animaux</term><term>Femelle</term><term>Foie (enzymologie)</term><term>Foie (métabolisme)</term><term>Glutathion (métabolisme)</term><term>Glycine (sang)</term><term>Génome</term><term>Humains</term><term>Lipoprotéines (métabolisme)</term><term>Modèles animaux de maladie humaine</term><term>Modélisation spécifique au patient</term><term>Mâle</term><term>Métabolomique ()</term><term>NAD (métabolisme)</term><term>Régulation de l'expression des gènes codant pour des enzymes</term><term>Souris</term><term>Stéatose hépatique non alcoolique (diétothérapie)</term><term>Stéatose hépatique non alcoolique (génétique)</term><term>Stéatose hépatique non alcoolique (métabolisme)</term><term>Sérine (administration et posologie)</term><term>Sérine (sang)</term><term>Sérine (usage thérapeutique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Serine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Glycine</term><term>Serine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glutathione</term><term>Lipoproteins</term><term>NAD</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Sérine</term></keywords><keywords scheme="MESH" qualifier="diet therapy" xml:lang="en"><term>Non-alcoholic Fatty Liver Disease</term></keywords><keywords scheme="MESH" qualifier="diétothérapie" xml:lang="fr"><term>Stéatose hépatique non alcoolique</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Foie</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Liver</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Non-alcoholic Fatty Liver Disease</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Stéatose hépatique non alcoolique</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Liver</term><term>Non-alcoholic Fatty Liver Disease</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Metabolomics</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Foie</term><term>Glutathion</term><term>Lipoprotéines</term><term>NAD</term><term>Stéatose hépatique non alcoolique</term></keywords><keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>Glycine</term><term>Sérine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Serine</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Sérine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Gene Expression Regulation, Enzymologic</term><term>Genome</term><term>Humans</term><term>Male</term><term>Mice</term><term>Middle Aged</term><term>Patient-Specific Modeling</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte d'âge moyen</term><term>Animaux</term><term>Femelle</term><term>Génome</term><term>Humains</term><term>Modèles animaux de maladie humaine</term><term>Modélisation spécifique au patient</term><term>Mâle</term><term>Métabolomique</term><term>Régulation de l'expression des gènes codant pour des enzymes</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Finlande</li><li>France</li><li>Pays-Bas</li><li>Suède</li></country><region><li>Bourgogne</li><li>Bourgogne-Franche-Comté</li><li>Hollande-Septentrionale</li><li>Svealand</li></region><settlement><li>Amsterdam</li><li>Dijon</li><li>Stockholm</li></settlement><orgName><li>Université d'Amsterdam</li></orgName></list><tree><country name="Suède"><region name="Svealand"><name sortKey="Mardinoglu, Adil" sort="Mardinoglu, Adil" uniqKey="Mardinoglu A" first="Adil" last="Mardinoglu">Adil Mardinoglu</name></region><name sortKey="Adiels, Martin" sort="Adiels, Martin" uniqKey="Adiels M" first="Martin" last="Adiels">Martin Adiels</name><name sortKey="Bjornson, Elias" sort="Bjornson, Elias" uniqKey="Bjornson E" first="Elias" last="Bjornson">Elias Bjornson</name><name sortKey="Boren, Jan" sort="Boren, Jan" uniqKey="Boren J" first="Jan" last="Boren">Jan Boren</name><name sortKey="Hallstrom, Bjorn M" sort="Hallstrom, Bjorn M" uniqKey="Hallstrom B" first="Björn M" last="Hallström">Björn M. Hallström</name><name sortKey="Klevstig, Martina" sort="Klevstig, Martina" uniqKey="Klevstig M" first="Martina" last="Klevstig">Martina Klevstig</name><name sortKey="Marschall, Hanns Ulrich" sort="Marschall, Hanns Ulrich" uniqKey="Marschall H" first="Hanns-Ulrich" last="Marschall">Hanns-Ulrich Marschall</name><name sortKey="Nielsen, Jens" sort="Nielsen, Jens" uniqKey="Nielsen J" first="Jens" last="Nielsen">Jens Nielsen</name><name sortKey="Smith, Ulf" sort="Smith, Ulf" uniqKey="Smith U" first="Ulf" last="Smith">Ulf Smith</name><name sortKey="St Hlman, Marcus" sort="St Hlman, Marcus" uniqKey="St Hlman M" first="Marcus" last="St Hlman">Marcus St Hlman</name><name sortKey="Uhlen, Mathias" sort="Uhlen, Mathias" uniqKey="Uhlen M" first="Mathias" last="Uhlén">Mathias Uhlén</name><name sortKey="Zhang, Cheng" sort="Zhang, Cheng" uniqKey="Zhang C" first="Cheng" last="Zhang">Cheng Zhang</name></country><country name="Finlande"><noRegion><name sortKey="Soderlund, Sanni" sort="Soderlund, Sanni" uniqKey="Soderlund S" first="Sanni" last="Söderlund">Sanni Söderlund</name></noRegion><name sortKey="Hakkarainen, Antti" sort="Hakkarainen, Antti" uniqKey="Hakkarainen A" first="Antti" last="Hakkarainen">Antti Hakkarainen</name><name sortKey="Lundbom, Jesper" sort="Lundbom, Jesper" uniqKey="Lundbom J" first="Jesper" last="Lundbom">Jesper Lundbom</name><name sortKey="Lundbom, Nina" sort="Lundbom, Nina" uniqKey="Lundbom N" first="Nina" last="Lundbom">Nina Lundbom</name><name sortKey="Taskinen, Marja Riitta" sort="Taskinen, Marja Riitta" uniqKey="Taskinen M" first="Marja-Riitta" last="Taskinen">Marja-Riitta Taskinen</name></country><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Kilicarslan, Murat" sort="Kilicarslan, Murat" uniqKey="Kilicarslan M" first="Murat" last="Kilicarslan">Murat Kilicarslan</name></region><name sortKey="Serlie, Mireille J" sort="Serlie, Mireille J" uniqKey="Serlie M" first="Mireille J" last="Serlie">Mireille J. Serlie</name></country><country name="France"><region name="Bourgogne-Franche-Comté"><name sortKey="Verges, Bruno" sort="Verges, Bruno" uniqKey="Verges B" first="Bruno" last="Vergès">Bruno Vergès</name></region></country><country name="Australie"><noRegion><name sortKey="Barrett, Peter Hugh R" sort="Barrett, Peter Hugh R" uniqKey="Barrett P" first="Peter Hugh R" last="Barrett">Peter Hugh R. Barrett</name></noRegion><name sortKey="Watts, Gerald F" sort="Watts, Gerald F" uniqKey="Watts G" first="Gerald F" last="Watts">Gerald F. Watts</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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