Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome

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 β-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-κB target genes and TGFβ/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.

Gut Microbiota Induced by Pterostilbene and Resveratrol in High-Fat-High-Fructose Fed Rats: Putative Role in Steatohepatitis Onset

“…This effect contributes to the hepato-protective properties of the polyphenol at the lowest dose. Moreover, a reduction in the abundance of Clostridum sensu stricto 1, whose link with NAFLD-related parameters has been reported elsewhere [51], was also observed in this group. This effect may well be driven by the antioxidant effect of pterostilbene, as reductions in Clostridum sensu stricto 1 abundance in response to antioxidant treatment (tempol) have been reported in a murine model of hepatic steatosis [52].…”

Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering

“…On the HFD, glycine was elevated with XOS supplementation. Impaired glycine biosynthesis has been linked with hyperlipidemia and steatohepatitis and, conversely, administration of glycine in a tripeptide form to mice alleviated both conditions [63]. Notably, the levels of hypoxanthine were decreased by XOS independent of dietary fat.…”

Role and Mechanism of Gut Microbiota in Human Disease

“…Studies have found that glycine may be directly related to the occurrence of NAFLD. Glycine significantly alleviates NAFLD in experimental mice by regulating fat oxidation, blood metabolite levels, gut microbiota composition, and glutathione synthesis (Rom et al, 2020). Furthermore, fibroblast growth factor-15/19 is a bile acid-induced gut hormone in the late fed phase that acts to decrease hepatic lipogenesis.…”