Endogenous bile acids are ligands for the nuclear receptor FXR BAR

The major metabolic pathway for elimination of cholesterol is via conversio n to bile acids. In addition to this metabolic function, bile acids also ac t as signaling molecules that negatively regulate their own biosynthesis. H owever, the precise nature of this signaling pathway has been elusive. We h ave isolated an endogenous biliary component (chenodeoxycholic acid) that s electively activates the orphan nuclear receptor, FXR. Structure-activity a nalysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the end ogenous bile acid sensor and thus an important regulator of cholesterol hom eostasis.