Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is within the spectrum of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). The prevalence of NASH is rising and has become a large burden to the medical system worldwide. Unfortunately, despite its high prevalence and severe health consequences, there is currently no therapeutic agent approved to treat NASH. Therefore, the development of efficacious therapies is of utmost urgency and importance. Many molecular targets are currently under investigation for their ability to halt NASH progression. One of the most promising and well-studied targets is the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR). In this chapter, the characteristics, etiology, and prevalence of NASH will be discussed. A brief introduction to FXR regulation of BA homeostasis will be described. However, for more details regarding FXR in BA homeostasis, please refer to previous chapters. In this chapter, the mechanisms by which tissue and cell type-specific FXR regulates NASH development will be discussed in detail. Several FXR agonists have reached later phase clinical trials for treatment of NASH. The progress of these compounds and summary of released data will be provided. Lastly, this chapter will address safety liabilities specific to the development of FXR agonists.