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

Journal article
Authors A. Mardinoglu
Elias Björnson
C. Zhang
Martina Klevstig
S. Soderlund
Marcus Ståhlman
Martin Adiels
A. Hakkarainen
N. Lundbom
M. Kilicarslan
B. M. Hallstrom
J. Lundbom
B. Verges
P. H. R. Barrett
G. F. Watts
M. J. Serlie
J. Nielsen
M. Uhlen
Ulf Smith
Hanns-Ulrich Marschall
M. R. Taskinen
Jan Borén
Published in Molecular Systems Biology
Volume 13
Issue 3
ISSN 1744-4292
Publication year 2017
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Language en
Keywords glutathione, NAFLD, personalized genome-scale metabolic modeling, serine, fatty liver-disease, amino-acid-metabolism, tissue blood-flow, adipose-tissue, genome-scale, insulin-resistance, hepatocellular-carcinoma, drug targets, obesity, muscle, Biochemistry & Molecular Biology, urenberg p, 1991, british journal of nutrition, v65, p105, zefsky t, 1976, journal of clinical investigation, v57, p444
Subject categories Biochemistry and Molecular Biology

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.

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