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LIVER AND BILIARY TRACT

Regulation of the mouse organic solute transporter -, Ost-Ost, by bile acids

¹Department of Pediatrics, Mount Sinai School of Medicine, New York, New York; and ²Department of Internal Medicine and Center for Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 11 October 2005 ; accepted in final form 9 December 2005

The mechanisms responsible for bile acid regulation of mouse intestinal organic solute transporter - (Ost-Ost) expression were investigated. Expression of Ost-Ost mRNA was increased in cecum and proximal colon of cholic acid-fed mice and in chenodeoxycholate-treated mouse CT26 colon adenocarcinoma cells. Sequence analysis revealed potential cis-acting elements for farnesoid X receptor (FXR) and liver receptor homolog-1 (LRH-1) in the mouse Ost and Ost promoters and reporter constructs containing Ost and Ost 5'-flanking sequences were positively regulated by bile acids. Expression of a dominant-negative FXR, reduction of FXR with interfering small RNA (siRNA), or mutation of the potential FXR elements decreased Ost and Ost promoter activity and abolished the induction by chenodeoxycolic acid. Negative regulation of the Ost and Ost promoters by bile acids was mediated through LRH-1 elements. Ost and Ost promoter activities were increased by coexpression of LRH-1 and decreased by coexpression of SHP. Mutation of the potential LRH-1 elements and siRNA-mediated reduction of LRH-1 expression decreased basal promoter activity. As predicted from the promoter analyses, ileal Ost and Ost mRNA expressions were increased in wild-type mice administered the FXR agonist GW4064 and decreased in FXR-null mice. Immunoblotting analysis revealed that Ost and Ost intestinal protein expressions correlated with mRNA expression. The mouse Ost and Ost promoters are unusual in that they contain functional FXR and LRH elements, which mediate, respectively, positive and negative feedback regulation by bile acids. Although the positive regulatory pathway appears to be dominant, this arrangement provides a mechanism to finely titrate Ost-Ost expression to the bile acid flux.

intestine; ileum; cecum; farnesoid X receptor; liver receptor homolog-1; small heterodimer partner; dynamic regulation

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