Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD
Artikel i vetenskaplig tidskrift, 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

Författare

Adil Mardinoglu

Chalmers, Biologi och bioteknik, Systembiologi

Elias Björnson

Chalmers, Biologi och bioteknik, Systembiologi

C. Zhang

Kungliga Tekniska Högskolan (KTH)

M. Klevstig

Sahlgrenska universitetssjukhuset

S. Soderlund

Helsinki University Central Hospital

Marcus Ståhlman

Sahlgrenska universitetssjukhuset

Martin Adiels

Sahlgrenska universitetssjukhuset

A. Hakkarainen

Helsinki University Central Hospital

N. Lundbom

Helsinki University Central Hospital

M. Kilicarslan

Universiteit Van Amsterdam

B. M. Hallstrom

Kungliga Tekniska Högskolan (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

Universiteit Van Amsterdam

Jens B Nielsen

Chalmers, Biologi och bioteknik, Systembiologi

M. Uhlen

Kungliga Tekniska Högskolan (KTH)

U. Smith

Sahlgrenska universitetssjukhuset

H. U. Marschall

Sahlgrenska universitetssjukhuset

M. R. Taskinen

Helsinki University Central Hospital

Jan Borén

Sahlgrenska universitetssjukhuset

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 13 3 916

Ämneskategorier

Farmaceutisk vetenskap

Biomedicinsk laboratorievetenskap/teknologi

Farmakologi och toxikologi

DOI

10.15252/msb.20167422