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

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. • Inhibiting liver ATP citrate lyase (ACLY) lowers cholesterol, steatosis, and fibrosis • GLP-1 receptor (GLP-1R) agonists lower body mass, glucose, and liver steatosis • In mice, combining a GLP-1R agonist and an ACLY inhibitor reduces NASH • Transcriptional signature of combo therapy is associated with fibrosis resolution Desjardins et al. find that combination therapy in mice with the ACLY inhibitor bempedoic acid and the GLP1-R agonist liraglutide leads to greater reductions in NASH and fibrosis than monotherapies and is associated with transcriptional signatures consistent with the resolution of liver fibrosis in clinical populations.