Farnesoid X receptor: from structure to potential clinical applications.

The farnesoid X receptor (FXR) is a well-characterized member of the “metabolic” subfamily of NRs. In 1999 FXR was recognized to be a transcriptional sensor for bile acids which are therefore witnessing their “renaissance” as signaling molecules after more than 20 years of research activity culminating with the clinical use of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) in the treatment of gallbladder stones and cholestatic liver diseases. Bile acids and oxysterols and cholestanoic acids are distinct classes of steroidal molecules derived from cholesterol. All of them act as signaling molecules and participate in an intricate network of interactions that ultimately govern lipid, steroid, and cholesterol homeostasis and are involved in processes such as glucose utilization, inflammation, and cancer. This Perspective will focus on the steps that led to the discovery and deorphanization of FXR and to the development of steroidal and nonsteroidal modulators, with a special emphasis given to the increasing therapeutic opportunities associated with FXR modulation