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

Adil Mardinoglu; Elias Bjornson; Cheng Zhang; Martin Klevstig; Sanni Söderlund; Marcus Ståhlman; Martin Adiels; Antti Hakkarainen; Nina Lundbom; Murat Kilicarslan; Björn M Hallström; Jesper Lundbom; Bruno Verges; Peter Hugh R Barrett; Gerald F Watts; Mireille J Serlie; Jens Nielsen; Mathias Uhlén; Ulf Smith; Hanns-Ulrich Marschall; Marja-Riitta Taskinen; Jan Boren

doi:10.15252/msb.20167422

Article dans une revue

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 [Gothenburg]

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

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Biochimie, Biologie Moléculaire

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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01561136
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Soumis le : mercredi 12 juillet 2017 - 13:55:35
Dernière modification le : jeudi 8 juillet 2021 - 03:43:13

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

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