Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model o f nonalcoholic steatohepatitis

Introduction: Nonalcoholic steatohepatitis (NASH) is largely driven by the dysregulation of liver metabolism and inflammation. Bile acids and their receptor Farnesoid X receptor (FXR) play a critical role in the disease development. Here, we investigated whether INT-767, the newly-identified dual FXR/TGR5 agonist, can protect rat from liver injury during NASH. Materials and methods: NASH model was established by feeding the male SD rats with high-fat diet for 16 weeks. INT-767 was given by gavage to NASH rats from week 13 to week 16. At the end of 16 weeks, liver and serum were harvested, and bile acids, glucose and lipid metabolism, liver injury and histological features were evaluated. Results: INT-767 treatment significantly alleviates high-fat caused liver damage characterized with lipid accumulation and hepatic infiltration of immune cells. INT-767 robustly restores the lipid, glucose metabolism to normal level, attenuates insulin resistance through upregulating FXR level and reverting the dysregulation of its target genes in liver metabolism. Molecularly INT-767 also attenuates the pro-inflammatory response by suppression of TNF-alpha and NF-kappa B signaling pathway. Conclusion: INT-767 may be an attractive candidate for a potential novel strategy on the treatment of NASH.