Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice

Cell Rep Med. 2023 Sep 19;4(9):101193. doi: 10.1016/j.xcrm.2023.101193.

Abstract

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 with 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.

Keywords: ACLY; GLP-1R agonist; MASH; NAFLD; NASH; bempedoic acid; combination treatment; fatty acid metabolism; hepatic fibrosis; lipogenesis; liraglutide; mouse model; semaglutide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases
  • Animals
  • Humans
  • Insulin Resistance*
  • Liver Cirrhosis / drug therapy
  • Mice
  • Non-alcoholic Fatty Liver Disease* / drug therapy

Substances

  • Acyltransferases