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

Adil Mardinoglu 1, 2, * Elias Bjornson 3, 4, 2 Cheng Zhang 2 Martin Klevstig 4 Sanni Söderlund 5 Marcus Ståhlman 4 Martin Adiels 4 Antti Hakkarainen 6, 7 Nina Lundbom 6 Murat Kilicarslan 8 Björn M Hallström 1 Jesper Lundbom 6, 7 Bruno Verges 9, 10 Peter Hugh R Barrett 11 Gerald F Watts Mireille J Serlie Jens Nielsen 12 Mathias Uhlén 13 Ulf Smith Hanns-Ulrich Marschall 14, 15 Marja-Riitta Taskinen Jan Boren 4, *
* Auteur correspondant
1 Science for Life Laboratory [Solna]
2 Department of Biology and Biological Engineering
3 Sahlgrenska University Hospital
4 Department of molecular and clinical medicine [Gothenburg]
5 University of Helsinki
6 Helsinki University Hospital
7 HUS-MIC - HUS Medical Imaging Center [Helsinki]
8 Department of Endocrinology and Metabolism (Academic Medical Center, Amsterdam)
9 Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon)
10 Equipe PADYS (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
11 Flow Interactive
12 Technical University of Denmark, National Institute of Aquatic Resources
13 Science for Life Laboratory
14 School of Earth Sciences [Bristol]
15 WHOI - Woods Hole Oceanographic Institution
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.
Keywords : serine NAFLD glutathione personalized genome‐scale metabolic modeling
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01561136
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mercredi 12 juillet 2017 - 13:55:35
Dernière modification le : jeudi 18 juin 2020 - 10:18:03

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UNIV-BOURGOGNE | LNC-UMR866 | LNC-PADYS

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Adil Mardinoglu, Elias Bjornson, Cheng Zhang, Martin Klevstig, Sanni Söderlund, et al.. Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.. Molecular Systems Biology, EMBO Press, 2017, 13, pp.916. ⟨10.15252/msb.20167422⟩. ⟨hal-01561136⟩

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