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Personal model-assisted identification of NAD(+) and glutathione metabolism as
intervention target in NAFLD
#MMPMID28254760
Mardinoglu A
; Bjornson E
; Zhang C
; Klevstig M
; Söderlund S
; Ståhlman M
; Adiels M
; Hakkarainen A
; Lundbom N
; Kilicarslan M
; Hallström BM
; Lundbom J
; Vergès B
; Barrett PH
; Watts GF
; Serlie MJ
; Nielsen J
; Uhlén M
; Smith U
; Marschall HU
; Taskinen MR
; Boren J
Mol Syst Biol
2017[Mar]; 13
(3
): 916
PMID28254760
show ga
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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