Bile acids are synthesized from cholesterol in the liver and are excreted into bile via the hepatocyte canalicular bile salt export pump. After their passage into the intestine, bile acids are reabsorbed in the ileum by sodium-dependent uptake across the apical membrane of enterocytes. At the basolateral domain of ileal enterocytes, bile acids are extruded into portal blood by the heterodimeric organic solute transporter OST alpha/ OST beta. Although the transport function of OST alpha/OST beta has been characterized, little is known about the regulation of its expression. We show here that human OST alpha/OST beta expression is induced by bile acids through ligand-dependent transactivation of both OST genes by the nuclear bile acid receptor/farnesoid X receptor ( FXR). FXR agonists induced endogenous mRNA levels of OST alpha and OST beta in cultured cells, an effect that was not discernible upon inhibition of FXR expression by small interfering RNAs. Furthermore, OST mRNAs were induced in human ileal biopsies exposed to the bile acid chenodeoxycholic acid. Reporter constructs containing OST alpha or OST alpha promoters were transactivated by FXR in the presence of its ligand. Two functional FXR binding motifs were identified in the OST alpha gene and one in the OST alpha gene. Targeted mutation of these elements led to reduced inducibility of both OST promoters by FXR. In conclusion, the genes encoding the human OST alpha/OST alpha complex are induced by bile acids and FXR. By coordinated control of OST alpha/OST alpha expression, bile acids may adjust the rate of their own efflux from enterocytes in response to changes in intracellular bile acid levels.
