Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD
Journal article, 2017

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.

genome-scale

hepatocellular-carcinoma

muscle

personalized genome-scale metabolic modeling

tissue blood-flow

amino-acid-metabolism

serine

insulin-resistance

drug targets

glutathione

adipose-tissue

fatty liver-disease

NAFLD

obesity

Author

Adil Mardinoglu

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Elias Björnson

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

C. Zhang

Royal Institute of Technology (KTH)

M. Klevstig

Sahlgrenska University Hospital

S. Soderlund

Helsinki University Central Hospital

Marcus Ståhlman

Sahlgrenska University Hospital

Martin Adiels

Sahlgrenska University Hospital

A. Hakkarainen

Helsinki University Central Hospital

N. Lundbom

Helsinki University Central Hospital

M. Kilicarslan

University of Amsterdam

B. M. Hallstrom

Royal Institute of Technology (KTH)

J. Lundbom

Helsinki University Central Hospital

B. Verges

Centre Hospitalier Universitaire de Dijon

P. H. R. Barrett

University of Western Australia

G. F. Watts

University of Western Australia

M. J. Serlie

University of Amsterdam

Jens B Nielsen

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

M. Uhlen

Royal Institute of Technology (KTH)

U. Smith

Sahlgrenska University Hospital

H. U. Marschall

Sahlgrenska University Hospital

M. R. Taskinen

Helsinki University Central Hospital

Jan Borén

Sahlgrenska University Hospital

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 13 3 916

Subject Categories

Pharmaceutical Sciences

Biomedical Laboratory Science/Technology

Pharmacology and Toxicology

DOI

10.15252/msb.20167422

More information

Latest update

9/6/2018 1