272-OR: Weight Loss with Time-Restricted Feeding or Treatment with Obeticholic Acid/Semaglutide Combination Have a Different Impact on Nonalcoholic Steatohepatitis in Diet-Induced Obese Mice

Introduction: Combination of therapies is a promising strategy for the treatment of NASH and liver fibrosis. Here we evaluated whether the Farnesoid X Receptor agonist obeticholic acid (OCA) combined with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (SEMA) would show superior effects than weight loss induction with time-restricted feeding (TRF) in mice. Methods: Mice were fed a 60% high fat/2% cholesterol diet with 10% fructose supplemented drinking water (HFCF diet) for 25 weeks to induce obesity and NASH/liver fibrosis. After the diet-induction period, mice were kept on HFCF diet and treated with vehicle (control) or OCA 30mg/kg p.o. QD + SEMA 0.06mg/kg s.c. QD, or placed on TRF from the last 3 hours of the dark cycle till the end of the light cycle, without access to food, but free access to normal drinking water (i.e. without fructose) every day, for 6 weeks. Results: OCA+SEMA induced a 20% lower caloric intake, which led to a 27% lower body weight (p<0.0vs. control) . TRF had a weaker effect on caloric intake (-9%) but also reduced body weight (-11%, p<0.vs. control) . Both OCA+SEMA and TRF reduced the HOMA-IR index of insulin resistance and significantly reduced plasma ALT and AST levels, but these effects were more pronounced with OCA+SEMA. TRF, and to a greater extent OCA+SEMA, significantly reduced liver weight, hepatic fatty acids, triglycerides, and total cholesterol levels. Both OCA+SEMA and TRF led to significantly lower NAFLD activity score. However, OCA+SEMA did not alter liver fibrosis, while TRF showed a clear anti-fibrotic effect in the liver, with lower % Sirius Red labelling (p<0.vs. control) . Conclusion: OCA+SEMA combination reduced body weight and NAFLD activity score but did not improve hepatic fibrosis, while TRF improved both NASH and liver fibrosis. These TRF benefits should be further investigated in obese NASH patients. Disclosure F.Briand: None. E.Grasset: None. N.Breyner: None. T.Sulpice: None.