Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of non-alcoholic steatohepatitis

Abstract

Aim: Non-alcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans.The present study aimed to evaluate a 3-week dietary mouse model of NASH and to validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH.Methods: C57BL6/J mice were fed a diet high in fat (60%), cholesterol (1.25%) and cholic acid (0.5%) along with 2% hydroxypropyl-β-cyclodextrin in drinking water (HFCC-CDX diet). Histological and biological parameters were measured at 1 and 3 weeks. Following 1-week diet induction, liraglutide was administrated daily for 2 weeks, and then NASH-associated phenotypic aspects were evaluated in comparison with control mice.Results: Prior to treatment with liraglutide, mice fed the HFCC-CDX diet for 1 week developed liver steatosis and had increased levels of oxidative-stress markers and hepatic and systemic inflammation.For mice not treated with liraglutide, these aspects were even more pronounced after 3 weeks of the dietary period, with additional liver insulin resistance and fibrosis. Liraglutide treatment corrected the diet-induced alterations in glucose metabolism and significantly reduced hepatic steatosis and inflammation. Conclusion:This study provides a novel 3-week dietary model of mice that rapidly develop NASH features, and this model will be suitable for evaluating the therapeutic efficacy of compounds in preclinical drug development for NASH.