Tropifexor‐Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents

• Published in: Hepatology communications Vol. 3; no. 8; pp. 1085 - 1097
• Main Authors: Hernandez, Eloy D., Zheng, Lianxing, Kim, Young, Fang, Bin, Liu, Bo, Valdez, Reginald A., Dietrich, William F., Rucker, Paul V., Chianelli, Donatella, Schmeits, James, Bao, Dingjiu, Zoll, Jocelyn, Dubois, Claire, Federe, Glenn C., Chen, Lihao, Joseph, Sean B., Klickstein, Lloyd B., Walker, John, Molteni, Valentina, McNamara, Peter, Meeusen, Shelly, Tully, David C., Badman, Michael K., Xu, Jie, Laffitte, Bryan
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins 01.08.2019; John Wiley and Sons Inc; Wolters Kluwer Health/LWW
• Subjects: Bile; Cytochrome; Experiments; Fibroblasts; Gene expression; Growth factors; Inflammation; Laboratory animals; Ligands; Lipids; Liver diseases; Metabolism; Metabolites; Mortality; Original; Oxidative stress; Polyethylene glycol; Polymerase chain reaction; Transplants & implants; Variance analysis; Japan
• DOI: 10.1002/hep4.1368
• ISSN: 2471-254X

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) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of the novel nonbile 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 (Stelic animal model [STAM]), tropifexor reversed established fibrosis and reduced the nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin‐resistant obese NASH model (amylin liver 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 that included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.