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, Ost-Ost, by Bile Acids
1 Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA
2 Department of Internal Medicine and Center for Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
* To whom correspondence should be addressed. E-mail: pdawson{at}wfubmc.edu.
The mechanisms responsible for bile acid regulation of mouse intestinal 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 FXR and LRH-1 in the mouse Ost and Ost promoters, and reporter constructs containing Ost and Ost 5[[rad]] flanking sequences were positively regulated by bile acids. Expression of a dominant negative FXR, siRNA-mediated reduction of FXR, or mutating the potential FXR elements decreased Ost and Ost promoter activity and abolished the induction by CDCA. Negative regulation of the Ost and Ost promoters by bile acids was mediated through LRH-1 elements. Ost and Ost promoter activity was increased by co-expression of LRH-1 and decreased by co-expression of SHP. Mutating 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 expression was 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 expression correlated with mRNA expression. The mouse Ost and Ost promoters are unusual in that they contain functional FXR and LRH elements, that respectively mediate positive and negative feedback regulation by bile acids. While the positive regulatory pathway appears to be dominant, this arrangement provides a mechanism to finely titrate Ost-Ost expression to the bile acid flux.
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