Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [NASH Custom panel]

Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH. For NanoString analysis, 4-5 RNA samples per group were inspected by a BioAnalyzer quality control test. The McMaster Genomics Facility ran an nCounter Fibrosis v2 Panel (NanoString Technologies) containing 760 target genes as well as a CustomSet Panel consisting of 22 orthologous mus musculus genes that correspond to the 25-gene NASH severity signature.