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

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Mardinoglu , A , Bjornson , E , Zhang , C , Klevstig , M , Söderlund , S , Ståhlman , M , Adiels , M , Hakkarainen , A , Lundbom , N , Kilicarslan , M , Hallström , B M , Lundbom , J , Verges , B , Barrett , P H R , Watts , G F , Serlie , M J , Nielsen , J , Uhlen , M , Smith , U , Marschall , H-U , Taskinen , M-R & Boren , J 2017 , ' Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD ' , Molecular Systems Biology , vol. 13 , no. 3 , 916 . https://doi.org/10.15252/msb.20167422

Title: Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD
Author: 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; Verges, Bruno; Barrett, Peter Hugh R.; Watts, Gerald F.; Serlie, Mireille J.; Nielsen, Jens; Uhlen, Mathias; Smith, Ulf; Marschall, Hanns-Ulrich; Taskinen, Marja-Riitta; Boren, Jan
Contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Department of Diagnostics and Therapeutics
University of Helsinki, Clinicum
Date: 2017-03
Language: eng
Number of pages: 17
Belongs to series: Molecular Systems Biology
ISSN: 1744-4292
URI: http://hdl.handle.net/10138/178654
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.
Subject: 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
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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