LXR Alpha Transactivates Mouse Organic Solute Transporter Alpha and Beta via IR-1 Elements Shared with FXR.

AbstractPurpose??Recently identified organic solute transporter (Ost) ? and ? 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?/? promoter-luciferase reporter constructs. Co-transfection of the constructs with farnesoid X receptor (FXR) and retinoid X receptor ? (RXR?) or liver X receptor ? (LXR?) and RXR? into Caco-2 cells induced the transcriptional activities of both Ost ? and ? and further increases were observed following treatment with each agonist. Sequence analyses indicated the presence of IR-1 regions in Ost? and Ost? promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXR?. Furthermore, mutations in IR-1 reduced the FXR- and LXR?-dependent transactivation of Ost?/?. Together with the detection of direct binding of FXR/RXR? and LXR?/RXR? to the IR-1 elements, the presence of functional FXRE/LXRE was revealed in the promoter region of both Ost? and Ost?. In addition, the stimulatory effect of FXR/RXR? and LXR?/RXR? on Ost?, but not on Ost?, was further enhanced by HNF-4?.Conclusions??It was concluded that LXR?/RXR? transcriptionally regulate mouse Ost?/? via IR-1 elements shared with FXR/RXR?. Exposure to FXR/LXR? modulators may affect the disposition of Ost?/? substrates. [ABSTRACT FROM AUTHOR]