The pathophysiological function of non-gastrointestinal farnesoid X receptor

Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.