Submitted on November 28, 2005
Accepted on January 11, 2006
Up-regulation of a Basolateral FXR-dependent Bile Acid Efflux Transporter, OST
-OST
, in Cholestasis in Humans and Rodents
James L. Boyer1*, Michael Trauner2, Albert Mennone1, Carol J. Soroka1, Shi-Ying Cai1, Tarek Moustafa2, Gernot Zollner2, Jin Young Lee3, and Nazzareno Ballatori3
1 Liver Center, Yale University School of Medicine, New Haven, CT, USA
2 Division of Gastroenterology and Hepatology, Department of Medicine, Medical University, Graz, Austria
3 Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: james.boyer{at}yale.edu.
OST
-OST
is a novel heterodimeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney and liver. To determine if OST-OST undergoes FXR dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild type mice. Hepatic OST and OST mRNA increased 3 and 32 fold respectively in patients with PBC compared to controls while expression of Ost and Ost also increased in the liver of rats and mice following CBDL. In contrast, expression of OST and OST mRNA was generally lower in Fxr null mice whereas CBDL failed to enhance expression of OST and OST when compared to wild type mice. HepG2 cells treated for 24 hours with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OST and OST mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ost and Ost are highly regulated in response to cholestatic liver injury and that this response is dependent on the FXR bile acid receptor.
