GSE129389
Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With Antioxidative Gene Expression Profile in Rodents
Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid–derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese NASH model (AMLN), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH. Overall design: Liver mRNA profiles of male C57BL/6 mice aged ~6 weeks and maintained on a high-fat (40% kcal; Primex), high-fructose (22% by weight), and high-cholesterol (2% by weight) diet (Research Diets Inc., New Brunswick, NJ; cat. no. D09100301) for 26 weeks to induce NASH. Control animals received low-fat diet (10% kcal) with no fructose or cholesterol (Research Diets; cat. no. D09100304). From week 26, animals received tropifexor (0.1, 0.3, or 0.9 mg/kg) or OCA (25 mg/kg) qd orally for 4 weeks.