LXR alpha transactivates mouse organic solute transporter alpha and beta via IR-1 elements shared with FXR

Purpose. Recently identified organic solute transporter (Ost) alpha and beta are located on the basolateral membrane of enterocytes and may be responsible for the intestinal absorption of many substrates including bile acids. In the present study, the mechanism governing the transcriptional regulation of their expression was investigated. Methods and Results. To clarify the transcriptional regulation of Osts, reporter gene assays were performed using mouse Ost alpha/beta promoter-luciferase reporter constructs. Co-transfection of the constructs with farnesoid X receptor (FXR) and retinoid X receptor alpha (RXR alpha) or liver X receptor alpha (LXR alpha) and RXR alpha into Caco-2 cells induced the transcriptional activities of both Ost alpha and beta and further increases were observed following treatment with each agonist. Sequence analyses indicated the presence of IR-1 regions in Ost alpha and Ost beta promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXR alpha. Furthermore, mutations in IR-1 reduced the FXR- and LXR alpha-dependent transactivation of Ost alpha/beta. Together with the detection of direct binding of FXR/RXR alpha and LXR alpha/RXR alpha to the IR-1 elements, the presence of functional FXRE/LXRE was revealed in the promoter region of both Ost alpha and Ost beta. In addition, the stimulatory effect of FXR/RXR alpha and LXR alpha/RXR alpha on Ost alpha, but not on Ost beta, was further enhanced by HNF-4 alpha. Conclusions. It was concluded that LXR alpha/RXR alpha transcriptionally regulate mouse Ost alpha/beta via IR-1 elements shared with FXR/RXR alpha. Exposure to FXR/LXR alpha modulators may affect the disposition of Ost alpha/beta substrates.