Abstract We0027: The pan-PPAR Agonist Lanifibranor Improves Dyslipidemia and MASH in a Diet-induced Obese Golden Syrian Hamster Model of Binge Drinking

Background: We aimed to validate an animal model to evaluate the efficacy of drugs targeting dyslipidemia and MASH in a context of moderate to heavy alcohol use, which may aggravate metabolic disturbances in patients with obesity and MASH. While mouse and rat are not convenient to study the effects of alcohol binge drinking, we previously observed that the golden Syrian hamster, which has a human-like lipoprotein metabolism, spontaneously shows a high preference for alcohol and may therefore represent a better preclinical model. Here we evaluated the effects of binge drinking (BD) and the effects of the pan-PPAR agonist lanifibranor (LANI) in diet-induced obese MASH hamsters. Methods: Diet-induced obese MASH hamsters were gavaged with saline (control) or with alcohol (40% alcohol at 10mL/kg p.o., 3 times per week) as BD, and were simultaneously treated with vehicle or LANI 30mg/kg p.o. QD for 5 weeks. Results: Compared to control, BD for 5 weeks in obese MASH hamsters did not alter hypercholesterolemia but aggravated hypertriglyceridemia, with greater fasting plasma triglycerides levels (p<0.001 vs. control). BD also raised hepatic inflammation and hepatocyte ballooning scores and led to greater liver fibrosis, as measured with % Sirius Red labelling (all p<0.05 vs. control). BD reduced the hepatic expression of genes involved in alcohol metabolism (Cyp2e1 and ADH1) and significantly raised the expression of genes involved in lipogenesis (ACC and SCD1), inflammation (IL-1b, IL-6, and MCP-1), cell death (caspase 3) and fibrosis (a-SMA, Col1a1, Col3a1 and TIMP1). Compared to obese hamsters treated with both BD and vehicle, LANI significantly lowered total cholesterol, LDL-cholesterol levels, and triglycerides plasma levels. Liver triglycerides content, hepatic inflammation and ballooning scores, as well as liver fibrosis were all reduced with LANI (all p<0.05 vs. vehicle). Additionally, LANI significantly reduced the hepatic expression of genes involved in inflammation and fibrosis. Conclusion: Binge drinking worsened hypertriglyceridemia and liver lesions, while LANI significantly improved dyslipidemia and MASH in obese hamsters. This preclinical model will help to evaluate drugs targeting dyslipidemia and MASH, in a context of moderate to heavy alcohol use, and their potential benefits in humans.