The organic solute transporter alpha-beta (OSTα/β) is a heteromeric transporter that is essential for bile acid and sterol disposition and for the enterohepatic circulation. To better understand the mechanism underlying OST gene regulation, the effects of retinoic acid (RA) on OSTα/β gene expression were investigated. The results show a dose-dependent induction of OSTβ, but not OSTα, expression in both Huh7 and HepG2 cells by RA treatment. A novel functional retinoic acid receptor response element (RARE, so-called DR5) in the promoter of OSTβ gene was identified. The interaction of RARα/RXRα with the RARE was verified by electrophoretic mobility shift and chromatin immunoprecipitation assays, and its functional importance by hOSTβ promoter activation in luciferase reporter assays. The studies demonstrated that the RARE is also a constitutive androstane receptor (CAR) binding site for OSTβ gene regulation. These results suggest that OSTβ is a target of both FXR-mediated (by binding to IR-1 element) and RARα- and CAR-mediated (by binding to DR5 element) gene regulation pathways. In summary, this study has uncovered a novel RARE (DR5) element in the promoter of OSTβ which binds RARα or CAR heterodimerized with RXRα, and appears to function synergistically with the IR-1 element to provide maximal induction of OSTβ in response to retinoic acid (RA). This finding demonstrates the physiological importance of RARα and CAR in controlling OSTβ expression levels.
- Copyright © 2013, American Journal of Physiology- Gastrointestinal and Liver Physiology