Abstract 145: Glycine Metabolism Links Atherosclerosis And NASH: Studies In Humans, Nonhuman Primates And Mice

Abstract

A major cause of death in patients with nonalcoholic steatohepatitis (NASH) is cardiovascular disease driven by accelerated atherosclerosis. The mechanisms linking NASH and atherosclerosis remain unclear and there is an urgent need to identify new pathways as targets for NASH without increasing, and preferably while decreasing, atherosclerosis. Lower circulating glycine is emerging as a common feature in both atherosclerosis and NASH, but the mechanisms behind reduced glycine, its potential as a causative factor and a therapeutic target are unclear. Applying unbiased transcriptomics and metabolomics, we uncovered impaired glycine biosynthesis in humans and mice with atherosclerosis and NASH. Hepatic glycine biosynthetic genes were downregulated with a most significant suppression of alanine-glyoxylate aminotransferase ( AGXT ). Functional deficiencies of AGXT lead to oxalate accumulation and we found decreased glycine/oxalate ratio in both NASH and atherosclerosis. In mice, dietary and genetic ( Agxt –/– and Agxt -/- / Apoe -/- ) approaches to limit glycine availability exacerbated NASH and atherosclerosis with suppressed hepatic fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. These effects were reversed by glycine supplementation and AAV8-mediated AGXT overexpression. We explored glycine-based compounds as potential therapies for atherosclerosis and NASH and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that protected mice from NASH and atherosclerosis by modulating FAO, glutathione synthesis and the gut microbiome. We further developed a dietary model in cynomolgus monkeys that closely mimics human NASH. DT-109 ameliorated NASH and showed anti-atherogenic properties in monkeys by modulating similar pathways observed in the mice. Altogether, impaired glycine metabolism links atherosclerosis and NASH and can be targeted for the simultaneous treatment of these diseases.