Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.
Identifieur interne : 001013 ( PubMed/Corpus ); précédent : 001012; suivant : 001014Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.
Auteurs : Adil Mardinoglu ; Elias Bjornson ; Cheng Zhang ; Martina Klevstig ; Sanni Söderlund ; Marcus St Hlman ; Martin Adiels ; Antti Hakkarainen ; Nina Lundbom ; Murat Kilicarslan ; Björn M. Hallström ; Jesper Lundbom ; Bruno Vergès ; Peter Hugh R. Barrett ; Gerald F. Watts ; Mireille J. Serlie ; Jens Nielsen ; Mathias Uhlén ; Ulf Smith ; Hanns-Ulrich Marschall ; Marja-Riitta Taskinen ; Jan BorenSource :
- Molecular systems biology [ 1744-4292 ] ; 2017.
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
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pubmed:28254760Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><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><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.</nlm:affiliation></affiliation></author><author><name sortKey="Bjornson, Elias" sort="Bjornson, Elias" uniqKey="Bjornson E" first="Elias" last="Bjornson">Elias Bjornson</name><affiliation><nlm:affiliation>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Cheng" sort="Zhang, Cheng" uniqKey="Zhang C" first="Cheng" last="Zhang">Cheng Zhang</name><affiliation><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Klevstig, Martina" sort="Klevstig, Martina" uniqKey="Klevstig M" first="Martina" last="Klevstig">Martina Klevstig</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Soderlund, Sanni" sort="Soderlund, Sanni" uniqKey="Soderlund S" first="Sanni" last="Söderlund">Sanni Söderlund</name><affiliation><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></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><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Adiels, Martin" sort="Adiels, Martin" uniqKey="Adiels M" first="Martin" last="Adiels">Martin Adiels</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Hakkarainen, Antti" sort="Hakkarainen, Antti" uniqKey="Hakkarainen A" first="Antti" last="Hakkarainen">Antti Hakkarainen</name><affiliation><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Lundbom, Nina" sort="Lundbom, Nina" uniqKey="Lundbom N" first="Nina" last="Lundbom">Nina Lundbom</name><affiliation><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Kilicarslan, Murat" sort="Kilicarslan, Murat" uniqKey="Kilicarslan M" first="Murat" last="Kilicarslan">Murat Kilicarslan</name><affiliation><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation></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><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Lundbom, Jesper" sort="Lundbom, Jesper" uniqKey="Lundbom J" first="Jesper" last="Lundbom">Jesper Lundbom</name><affiliation><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Verges, Bruno" sort="Verges, Bruno" uniqKey="Verges B" first="Bruno" last="Vergès">Bruno Vergès</name><affiliation><nlm:affiliation>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.</nlm:affiliation></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><nlm:affiliation>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.</nlm:affiliation></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><nlm:affiliation>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.</nlm:affiliation></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><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Nielsen, Jens" sort="Nielsen, Jens" uniqKey="Nielsen J" first="Jens" last="Nielsen">Jens Nielsen</name><affiliation><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Uhlen, Mathias" sort="Uhlen, Mathias" uniqKey="Uhlen M" first="Mathias" last="Uhlén">Mathias Uhlén</name><affiliation><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Smith, Ulf" sort="Smith, Ulf" uniqKey="Smith U" first="Ulf" last="Smith">Ulf Smith</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></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><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></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><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Boren, Jan" sort="Boren, Jan" uniqKey="Boren J" first="Jan" last="Boren">Jan Boren</name><affiliation><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></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></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><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.</nlm:affiliation></affiliation></author><author><name sortKey="Bjornson, Elias" sort="Bjornson, Elias" uniqKey="Bjornson E" first="Elias" last="Bjornson">Elias Bjornson</name><affiliation><nlm:affiliation>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Cheng" sort="Zhang, Cheng" uniqKey="Zhang C" first="Cheng" last="Zhang">Cheng Zhang</name><affiliation><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Klevstig, Martina" sort="Klevstig, Martina" uniqKey="Klevstig M" first="Martina" last="Klevstig">Martina Klevstig</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Soderlund, Sanni" sort="Soderlund, Sanni" uniqKey="Soderlund S" first="Sanni" last="Söderlund">Sanni Söderlund</name><affiliation><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></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><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Adiels, Martin" sort="Adiels, Martin" uniqKey="Adiels M" first="Martin" last="Adiels">Martin Adiels</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Hakkarainen, Antti" sort="Hakkarainen, Antti" uniqKey="Hakkarainen A" first="Antti" last="Hakkarainen">Antti Hakkarainen</name><affiliation><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Lundbom, Nina" sort="Lundbom, Nina" uniqKey="Lundbom N" first="Nina" last="Lundbom">Nina Lundbom</name><affiliation><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Kilicarslan, Murat" sort="Kilicarslan, Murat" uniqKey="Kilicarslan M" first="Murat" last="Kilicarslan">Murat Kilicarslan</name><affiliation><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation></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><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Lundbom, Jesper" sort="Lundbom, Jesper" uniqKey="Lundbom J" first="Jesper" last="Lundbom">Jesper Lundbom</name><affiliation><nlm:affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Verges, Bruno" sort="Verges, Bruno" uniqKey="Verges B" first="Bruno" last="Vergès">Bruno Vergès</name><affiliation><nlm:affiliation>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.</nlm:affiliation></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><nlm:affiliation>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.</nlm:affiliation></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><nlm:affiliation>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.</nlm:affiliation></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><nlm:affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Nielsen, Jens" sort="Nielsen, Jens" uniqKey="Nielsen J" first="Jens" last="Nielsen">Jens Nielsen</name><affiliation><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Uhlen, Mathias" sort="Uhlen, Mathias" uniqKey="Uhlen M" first="Mathias" last="Uhlén">Mathias Uhlén</name><affiliation><nlm:affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Smith, Ulf" sort="Smith, Ulf" uniqKey="Smith U" first="Ulf" last="Smith">Ulf Smith</name><affiliation><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></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><nlm:affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</nlm:affiliation></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><nlm:affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</nlm:affiliation></affiliation></author><author><name sortKey="Boren, Jan" sort="Boren, Jan" uniqKey="Boren J" first="Jan" last="Boren">Jan Boren</name><affiliation><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></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="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="diet therapy" xml:lang="en"><term>Non-alcoholic Fatty Liver Disease</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="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" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Serine</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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28254760</PMID><DateCreated><Year>2017</Year><Month>03</Month><Day>03</Day></DateCreated><DateCompleted><Year>2017</Year><Month>07</Month><Day>31</Day></DateCompleted><DateRevised><Year>2017</Year><Month>07</Month><Day>31</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1744-4292</ISSN><JournalIssue CitedMedium="Internet"><Volume>13</Volume><Issue>3</Issue><PubDate><Year>2017</Year><Month>Mar</Month><Day>02</Day></PubDate></JournalIssue><Title>Molecular systems biology</Title><ISOAbbreviation>Mol. Syst. Biol.</ISOAbbreviation></Journal><ArticleTitle>Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.</ArticleTitle><Pagination><MedlinePgn>916</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.15252/msb.20167422</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>© 2017 The Authors. Published under the terms of the CC BY 4.0 license.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mardinoglu</LastName><ForeName>Adil</ForeName><Initials>A</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4254-6090</Identifier><AffiliationInfo><Affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bjornson</LastName><ForeName>Elias</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Cheng</ForeName><Initials>C</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-3721-8586</Identifier><AffiliationInfo><Affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Klevstig</LastName><ForeName>Martina</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Söderlund</LastName><ForeName>Sanni</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ståhlman</LastName><ForeName>Marcus</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Adiels</LastName><ForeName>Martin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hakkarainen</LastName><ForeName>Antti</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lundbom</LastName><ForeName>Nina</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kilicarslan</LastName><ForeName>Murat</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hallström</LastName><ForeName>Björn M</ForeName><Initials>BM</Initials><AffiliationInfo><Affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lundbom</LastName><ForeName>Jesper</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vergès</LastName><ForeName>Bruno</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Barrett</LastName><ForeName>Peter Hugh R</ForeName><Initials>PH</Initials><AffiliationInfo><Affiliation>Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Watts</LastName><ForeName>Gerald F</ForeName><Initials>GF</Initials><AffiliationInfo><Affiliation>Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Serlie</LastName><ForeName>Mireille J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nielsen</LastName><ForeName>Jens</ForeName><Initials>J</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-9955-6003</Identifier><AffiliationInfo><Affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Uhlén</LastName><ForeName>Mathias</ForeName><Initials>M</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4858-8056</Identifier><AffiliationInfo><Affiliation>Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smith</LastName><ForeName>Ulf</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marschall</LastName><ForeName>Hanns-Ulrich</ForeName><Initials>HU</Initials><AffiliationInfo><Affiliation>Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Taskinen</LastName><ForeName>Marja-Riitta</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Research programs Unit, Diabetes and Obesity, 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