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

• Published in: Molecular systems biology Vol. 13; no. 3; pp. 916 - n/a
• Main Authors: Mardinoglu, Adil, Bjornson, Elias, Zhang, Cheng, Klevstig, Martina, Söderlund, Sanni, Ståhlman, Marcus, Adiels, Martin, Hakkarainen, Antti, Lundbom, Nina, Kilicarslan, Murat, Hallström, Björn M, Lundbom, Jesper, Vergès, Bruno, Barrett, Peter Hugh R, Watts, Gerald F, Serlie, Mireille J, Nielsen, Jens, Uhlén, Mathias, Smith, Ulf, Marschall, Hanns‐Ulrich, Taskinen, Marja‐Riitta, Boren, Jan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2017; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: 1976; 1991; adipose-tissue; amino-acid-metabolism; Animals; Apolipoproteins; Biochemistry & Molecular Biology; Biosynthesis; Body mass index; british journal of nutrition; Cholesterol; Demand analysis; Dietary supplements; Disease Models, Animal; drug targets; EMBO17; EMBO21; EMBO42; Fasting; Fatty liver; fatty liver-disease; Female; Fluxes; Gene expression; Gene Expression Regulation, Enzymologic; Genome; genome-scale; Genomes; Glutathione; Glutathione - metabolism; Glycine; Glycine - blood; hepatocellular-carcinoma; Humans; Insulin resistance; journal of clinical investigation; Laboratory animals; Life Sciences; Lipids; Lipoproteins - metabolism; Liver; Liver - enzymology; Liver - metabolism; Liver diseases; Male; Metabolism; Metabolites; Metabolomics; Metabolomics - methods; Mice; Middle Aged; Molecular Biology; Molecular modelling; Molekylärbiologi; muscle; NAD; NAD - metabolism; NAFLD; Non-alcoholic Fatty Liver Disease - diet therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; obesity; p105; p444; Patient-Specific Modeling; personalized genome-scale metabolic modeling; Plasma levels; Precursors; Serine; Serine - administration & dosage; Serine - blood; Serine - therapeutic use; Steatosis; tissue blood-flow; Triglycerides; urenberg p; v57; v65; zefsky t; United States > US; serine; NAFLD; personalized genome‐scale metabolic modeling; glutathione
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20167422

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. Synopsis Personalized modeling and metabolic measurements identified altered GSH and NAD + metabolism as a prevailing feature in NAFLD. These findings suggested a potential treatment strategy for NAFLD patients based on increased oxidation of fat and increased synthesis of GSH. We developed personalized genome‐scale metabolic models for NAFLD patients. We found that altered GSH and NAD + metabolism is a prevailing feature in NAFLD. Plasma and liver levels of glycine and serine were lower in NAFLD patients. Supplementation of precursors for glutathione and NAD + decreased HS in mice. Serine supplementation decreased liver fat and improved markers of liver function in humans. Graphical Abstract Personalized modeling and metabolic measurements identified altered GSH and NAD + metabolism as a prevailing feature in NAFLD. These findings suggested a potential treatment strategy for NAFLD patients based on increased oxidation of fat and increased synthesis of GSH.