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Am J Physiol Gastrointest Liver Physiol (November 3, 2005). doi:10.1152/ajpgi.00430.2005
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Submitted on September 12, 2005
Accepted on October 31, 2005

The Nuclear Receptor for Bile Acids, FXR, Transactivates the Human Organic Solute Transporter -{alpha} and -{beta} Genes

Jean-Francois Landrier1, Jyrki J. Eloranta1, Stephan R. Vavricka1, and Gerd A. Kullak-Ublick1*

1 Laboratory of Molecular Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland

* To whom correspondence should be addressed. E-mail: gerd.kullak{at}usz.ch.

Bile acids are synthesized from cholesterol in the liver and are excreted into bile via the hepatocyte canalicular bile salt export pump. Following 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). The FXR agonists induced endogenous mRNA levels of OST{alpha} and OST{beta} in cultured cells, an effect that was not discernible upon inhibiting FXR expression by small interfering RNAs. Furthermore, the OST mRNAs were induced in human ileal biopsies exposed to the bile acid chenodeoxycholic acid. Reporter constructs containing the OST{alpha} or OST{beta} 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{beta} 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{beta} complex are induced by bile acids and FXR. By coordinated control of OST{alpha}/OST{beta} expression, bile acids may adjust the rate of their own efflux from enterocytes in response to changes in intracellular bile acid levels.




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