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Mol Syst Biol. 2017 Mar 2;13(3):916. doi: 10.15252/msb.20167422.

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

Author information

1
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.
2
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
3
Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden.
4
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
5
Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
6
Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
7
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
8
Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France.
9
Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia.
10
Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
11
Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden adilm@scilifelab.se jan.boren@wlab.gu.se.

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:

NAFLD ; glutathione; personalized genome‐scale metabolic modeling; serine

Comment in

PMID:
28254760
PMCID:
PMC5371732
DOI:
10.15252/msb.20167422
[Indexed for MEDLINE]
Free PMC Article

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