The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter- and - genes

Landrier, Jean-François, Jyrki J. Eloranta, Stephan R. Vavricka, and Gerd A. Kullak-Ublick. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporterand genes. Am J Physiol Gastrointest Liver Physiol 290: G476–G485, 2006. First published November 3, 2005; doi:10.1152/ajpgi.00430.2005.—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 sodiumdependent 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 / OST . Although the transport function of OST /OST has been characterized, little is known about the regulation of its expression. We show here that human OST /OST 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 and OST 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 or OST promoters were transactivated by FXR in the presence of its ligand. Two functional FXR binding motifs were identified in the OST gene and one in the OST gene. Targeted mutation of these elements led to reduced inducibility of both OST promoters by FXR. In conclusion, the genes encoding the human OST /OST complex are induced by bile acids and FXR. By coordinated control of OST /OST expression, bile acids may adjust the rate of their own efflux from enterocytes in response to changes in intracellular bile acid levels.