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

Research output: Contribution to journalArticle

Adil Mardinoglu, Elias Bjornson, Cheng Zhang, Martina Klevstig, Sanni Soderlund, Marcus Stahlman, Martin Adiels, Antti Hakkarainen, Nina Lundbom, Murat Kilicarslan, Bjorn M. Hallstrom, Jesper Lundbom, Bruno Verges, Peter Hugh R. Barrett, Gerald F. Watts, Mireille J. Serlie, Jens Nielsen, Mathias Uhlen, Ulf Smith, Hanns-Ulrich Marschall & 2 more Marja-Riitta Taskinen, Jan Boren

Original languageEnglish
JournalMolecular Systems Biology
Volume13
Issue number3
Early online date2 Mar 2017
DOIs
Publication statusPublished - Mar 2017

King's Authors

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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