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Publication
Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation,
glutathione synthesis, and the gut microbiome.
Authors Rom O, Liu Y, Liu Z, Zhao Y, Wu J, Ghrayeb A, Villacorta L, Fan Y, Chang L, Wang
L, Liu C, Yang D, Song J, Rech JC, Guo Y, Wang H, Zhao G, Liang W, Koike Y, Lu
H, Koike T, Hayek T, Pennathur S, Xi C, Wen B, Sun D, Garcia-Barrio MT, Aviram
M, Gottlieb E, Mor I, Liu W, Zhang J, Chen YE
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Science translational medicine
Year 2020
Date Published 12/1/2020
Volume : Pages 12 : Not Specified
PubMed Reference 33268508
Abstract Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis
(NASH) has reached epidemic proportions with no pharmacological therapy
approved. Lower circulating glycine is consistently reported in patients with
NAFLD, but the causes for reduced glycine, its role as a causative factor, and
its therapeutic potential remain unclear. We performed transcriptomics in livers
from humans and mice with NAFLD and found suppression of glycine biosynthetic
genes, primarily alanine-glyoxylate aminotransferase 1 (AGXT1). Genetic
(Agxt1-/- mice) and dietary approaches to limit glycine availability resulted in
exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed
mitochondrial/peroxisomal fatty acid ß-oxidation (FAO) and enhanced inflammation
as the underlying pathways. We explored glycine-based compounds with dual
lipid/glucose-lowering properties as potential therapies for NAFLD and
identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition
and lowered circulating glucose, lipids, transaminases, proinflammatory
cytokines, and steatohepatitis in mice with established NASH induced by a
high-fat, cholesterol, and fructose diet. We applied metagenomics,
transcriptomics, and metabolomics to explore the underlying mechanisms. The
bacterial genus Clostridium sensu stricto was markedly increased in mice with
NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways,
lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn,
inflammatory infiltration and hepatic fibrosis were attenuated via suppression
of NF-?B target genes and TGFß/SMAD signaling. Unlike its effects on the gut
microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH.
In conclusion, impaired glycine metabolism may play a causative role in NAFLD.
Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO
and glutathione synthesis, thus warranting clinical evaluation.




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