title: Personal model-assisted identification of NAD+and glutathione metabolism as intervention target in NAFLD.
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 alteredde novoGSH 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.
authors.affiliation: Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.|Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Adil
authors.identifier: 0000-0002-4254-6090
authors.initials: A
authors.lastname: Mardinoglu
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Elias
authors.initials: E
authors.lastname: Bjornson
authors.affiliation: Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Cheng
authors.identifier: 0000-0002-3721-8586
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Klevstig
authors.affiliation: Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Sanni
authors.initials: S
authors.lastname: Söderlund
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Adiels
authors.affiliation: Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Hakkarainen
authors.affiliation: Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Lundbom
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Murat
authors.initials: M
authors.lastname: Kilicarslan
authors.affiliation: Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Björn M
authors.initials: BM
authors.lastname: Hallström
authors.affiliation: Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Jesper
authors.initials: J
authors.lastname: Lundbom
authors.affiliation: Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vergès
authors.affiliation: Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.
authors.forename: Peter Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.affiliation: Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mireille J
authors.initials: MJ
authors.lastname: Serlie
authors.affiliation: Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.|Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Jens
authors.identifier: 0000-0002-9955-6003
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Mathias
authors.identifier: 0000-0002-4858-8056
authors.initials: M
authors.lastname: Uhlén
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Boren
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D016678:Genome; D005978:Glutathione / Q000378:metabolism*; D005998:Glycine / Q000097:blood; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008875:Middle Aged; D009243:NAD / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000178:diet therapy / Q000235:genetics* / Q000378:metabolism; D066230:Patient-Specific Modeling; D012694:Serine / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use
chemical_list: D008074:Lipoproteins; D009243:NAD; D012694:Serine; D005978:Glutathione; D005998:Glycine
keywords: 
  NAFLD
  ; glutathione; personalized genome‐scale metabolic modeling; serine