Regulation of the mouse organic solute transporter α-β, Ostα-Ostβ, by bile acids

The mechanisms responsible for bile acid regulation of mouse intestinal organic solute transporter alpha-beta (Ost alpha-Ost beta) expression were investigated. Expression of Ost alpha-Ost beta 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 alpha and Ost beta promoters and reporter constructs containing Ost alpha and Ost beta 5'-flanking sequences were positively regulated by bile acids. Expression of a dominant-negative FXR, reduction of FXR with interfering small RNA (ssiRNA), or mutation of the potential FXR elements decreased Ost alpha and Ost beta promoter activity and abolished the induction by chenodeoxycolic acid. Negative regulation of the Ost alpha and Ost beta promoters by bile acids was mediated through LRH-1 elements. Ost alpha and Ost beta 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 alpha and Ost beta mRNA expressions were increased in wild-type mice administered the FXR agonist GW4064 and decreased in FXR-null mice. Immunoblotting analysis revealed that Ost alpha and Ost beta intestinal protein expressions correlated with mRNA expression. The mouse Ost alpha and Ost beta 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 alpha-Ost beta expression to the bile acid flux.