Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD

Autor: Mardinoglu , Adil, Bjornson , Elias, Zhang , Cheng, Klevstig , Martin, Söderlund , Sanni, Ståhlman , Marcus, Adiels , Martin, Hakkarainen , Antti, Lundbom , Nina, Kilicarslan , Murat, Hallström , Björn M, Lundbom , Jesper, Verges , Bruno, Barrett , Peter Hugh R, Watts , Gerald F, Serlie , Mireille J, Nielsen , Jens, Uhlén , Mathias, Smith , Ulf, Marschall , Hanns-Ulrich, Taskinen , Marja-Riitta, Boren , Jan
Přispěvatelé: Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Endocrinology, Science for Life Laboratory [Solna], Royal Institute of Technology [Stockholm] ( KTH ), Department of Biology and Biological Engineering, Chalmers University of Technology [Göteborg], Sahlgrenska University Hospital, Department of molecular and clinical medicine [Gothenburg], University of Gothenburg ( GU ), University of Helsinki [Helsinki], Helsinki University Hospital, HUS Medical Imaging Center (Helsinky), University of Helsinki [Helsinki]-Helsinki University Central Hospital, Department of Endocrinology and Metabolism (Academic Medical Center, Amsterdam), Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Equipe PADYS (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Flow Interactive, Technical University of Denmark, National Institute of Aquatic Resources, Science for Life Laboratory, Royal Institute of Technology in Stockholm ( KTH ), School of Earth Sciences [Bristol], University of Bristol [Bristol], Woods Hole Oceanographic Institution ( WHOI ), Royal Institute of Technology [Stockholm] (KTH ), Sahlgrenska University Hospital [Gothenburg], University of Gothenburg (GU), University of Helsinki, HUS Medical Imaging Center [Helsinki] (HUS-MIC), HiLIFE - Neuroscience Center (NC), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki-Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Royal Institute of Technology in Stockholm (KTH), Woods Hole Oceanographic Institution (WHOI), HUS Internal Medicine and Rehabilitation, Research Programs Unit, Diabetes and Obesity Research Program, Clinicum, Department of Diagnostics and Therapeutics, HUS Medical Imaging Center, Marja-Riitta Taskinen Research Group, Helsinki University Hospital Area, HUS Heart and Lung Center
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Molecular systems biology, 13(3). Wiley-Blackwell
Molecular Systems Biology
Molecular Systems Biology, EMBO Press, 2017, 13, pp.916. 〈http://msb.embopress.org/content/13/3/916〉. 〈10.15252/msb.20167422〉
Molecular Systems Biology, EMBO Press, 2017, 13, pp.916. ⟨10.15252/msb.20167422⟩
ISSN: 1744-4292
DOI: 10.15252/msb.20167422〉
Popis: IF 10.5; International audience; 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.
Databáze: OpenAIRE
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