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