FXR and NASH: an avenue for tissue-specific regulation

NASH is within the spectrum of NAFLD, a liver condition encompassing liver steatosis, inflammation, hepatocyte injury, and fibrosis. The prevalence of NASH-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. There is no Food and Drug Administration (FDA)-approved pharmacological intervention for NASH. The farnesoid X receptor (FXR) is essential in regulating bile acid homeostasis, and dysregulation of bile acids has been implicated in the pathogenesis of NASH. As a result, modulators of FXR that show desirable effects in mitigating key characteristics of NASH have been developed as promising therapeutic approaches. However, global FXR activation causes adverse effects such as cholesterol homeostasis imbalance and pruritus. The development of targeted FXR modulation is necessary for ideal NASH therapeutics, but information regarding tissue-specific and cell-specific FXR functionality is limited. In this review, we highlight FXR activation in the regulation of bile acid homeostasis and NASH development, examine the current literature on tissue-specific regulation of nuclear receptors, and speculate on how FXR regulation will be beneficial in the treatment of NASH. Export