2488-P: Glucagon Agonism Alleviates Hepatic Steatosis, Fibrosis, and Inflammation

Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) has limited effective treatments. Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, reduces liver fat with little effect on fibrosis or inflammation. Hepatocytes do not express the GLP-1R and it is unclear whether semaglutide's effects are dependent of weight loss. Hepatocytes express the glucagon receptor (GCGR) and agonism increases catabolic metabolism including lipid oxidation. GCGR:GLP-1R co-agonism is being pursued for the treatment of obesity and MASH, yet, how GCGR agonism affects features of MASH remains unclear. Moreover, patients with MASH may display hepatic GCGR resistance, which could limit the use of GCGR agonism. We hypothesized that chronic GCGR agonism would improve hepatic steatosis, fibrosis and inflammation in a mouse model of MASH; and tested whether the effects of GLP-1R agonist are weight-dependent Methods: We fed mice MASH-inducing diet for 23 weeks and then chronically agonized the GLP-1R (semaglutide) and GCGR (IUB288), alone and in combination, for 3 weeks and assessed MASH parameters. To test for weight-dependent effects, we repeated these studies in mice deficient for the Glp1r in glutamatergic neurons (Glp1rVGLUT2-/- ), a model where semaglutide treatment fails to reduce body weight. Results: Hepatic GCGR signaling after acute IUB288 agonism was significantly reduced in mice fed a MASH-inducing diet, suggesting a degree of GCGR resistance. After chronic agonism, all treated groups lost weight compared to PBS controls. Steatosis was reduced in all treated groups compared to controls. Fibrosis was only reduced in the IUB288 alone and combination groups. Weight loss in response to semaglutide treatment was significantly reduced in Glp1rVGLUT2-/- compared to controls. Ongoing tissue analysis will determine the weight dependent effects on MASH outcomes for semaglutide. Conclusion: Our data indicates that GCGR agonism alleviates steatosis and fibrosis and provides support for GCGR agonism as a therapeutic means for improving features of MASH. Disclosure S.A. Hannou: Research Support; Current; Merck Sharp & Dohme Corp. D. Bouslov: None. S.P. Ferrano: None. D. Leander: None. D. Wothe: None. R.A. Hollander: None. M. Paisley: None. A. Chen: None. P.J. White: Consultant; Current; XW Pharma. Research Support; Ended; Merck & Co., Inc. D.M. D'Alessio: Other - Clinical Trials; Current; Eli Lilly and Company. Consultant; Current; Sun Pharmaceutical Industries Ltd., Vertex Pharmaceuticals Incorporated. J. Campbell: Research Support; Current; Eli Lilly and Company. Research Support; Ended; Novo Nordisk. Research Support; Current; Merck & Co., Inc., Structure Therapeutics, Protagonist Therapeutics, Prostasis. Consultant; Current; Roche Pharmaceuticals, Neurocrine Biosciences, Inc., Arrowhead Pharmaceuticals, Boehringer Ingelheim International GmbH. Funding Research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA”.