Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.