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

Eric M Desjardins; Jianhan Wu; Declan C T Lavoie; Elham Ahmadi; Logan K Townsend; Marisa R Morrow; Dongdong Wang; Evangelia E Tsakiridis; Battsetseg Batchuluun; Russta Fayyazi; Jacek M Kwiecien; Theodoros Tsakiridis; James S V Lally; Guillaume Paré; Stephen L Pinkosky; Gregory R Steinberg

doi:10.1016/j.xcrm.2023.101193

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.

Authors

Eric M Desjardins¹, Jianhan Wu², Declan C T Lavoie¹, Elham Ahmadi¹, Logan K Townsend¹, Marisa R Morrow¹, Dongdong Wang¹, Evangelia E Tsakiridis¹, Battsetseg Batchuluun¹, Russta Fayyazi¹, Jacek M Kwiecien³, Theodoros Tsakiridis⁴, James S V Lally¹, Guillaume Paré⁵, Stephen L Pinkosky⁶, Gregory R Steinberg⁷

Affiliations

¹ Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
² Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada; Population Health Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada.
³ Department of Pathology, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁴ Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Department of Oncology, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Population Health Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada.
⁶ Esperion Therapeutics, Inc., Ann Arbor, MI, USA.
⁷ Centre for Metabolism Obesity and Diabetes Research, McMaster University, Hamilton ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8L 2X2, Canada. Electronic address: gsteinberg@mcmaster.ca.

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

Grants and funding

201709FDN-CEBA-116200/CIHR/Canada