0 avis
A 3-week nonalcoholic steatohepatitis mouse model allows the rapid evaluation of liraglutide and elafibranor benefits on NASH
Archive ouverte
International audience. Background: The long duration of animal models represents a clear limitation to rapidly evaluate the efficacy of drugs targeting nonalcoholic steatohepatitis (NASH). We therefore developed a rapid mouse model fed a 60% high fat, 1.25% cholesterol, 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX diet), to induce NASH and liver fibrosis within 3 weeks. To demonstrate the relevance of the model, the curative effects of the GLP-1 receptor agonist liraglutide (LIRA) and the dual PPAR alpha/delta agonist elafibranor (ELA) were evaluated. Methods: After 1 week of HFCC/CDX diet to induce liver steatosis, inflammation, oxidative stress and hepatic insulin resistance, mice were kept on diet and treated with vehicle, LIRA 0.1mg/kg QD or ELA 20mg/kg QD for 2 weeks. Results: Compared with vehicle, treatment with LIRA significantly restored hepatic insulin sensitivity, and significantly reduced liver triglycerides levels, oxidative stress and lipid peroxidation. Additionally, LIRA significantly reduced hepatic steatosis, inflammation and total NAS score, but did not reduced hepatic portal fibrosis. Compared with vehicle, ELA markedly reduced hepatic steatosis, inflammation, fibrosis and total NAS scores (all p<0.001 vs. vehicle). ELA significantly attenuated the HFCC/CDX diet-induced increase of liver Kupffer cells, monocytes and dendritic cells. Hepatic necroptosis and apoptosis were also reduced, with significantly higher cleaved RIP3 and lower cleaved caspase 3 protein levels (both p<0.05 vs. vehicle). Conclusion: In our 3-week NASH mouse model, both LIRA and ELA demonstrated benefits on NASH. This rapid animal model will be useful to rapidly detect the effects of novel drugs targeting NASH.
Consulter en ligne
Suggestions
Du même auteur
