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 Ostalpha/beta promoter-luciferase reporter constructs. Co-transfection of the constructs with farnesoid X receptor (FXR) and retinoid X receptor alpha (RXRalpha) or liver X receptor alpha (LXRalpha) and RXRalpha 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 Ostalpha and Ostbeta promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXRalpha. Furthermore, mutations in IR-1 reduced the FXR- and LXRalpha-dependent transactivation of Ostalpha/beta. Together with the detection of direct binding of FXR/RXRalpha and LXRalpha/RXRalpha to the IR-1 elements, the presence of functional FXRE/LXRE was revealed in the promoter region of both Ostalpha and Ostbeta. In addition, the stimulatory effect of FXR/RXRalpha and LXRalpha/RXRalpha on Ostalpha, but not on Ostbeta, was further enhanced by HNF-4alpha.
Conclusions: It was concluded that LXRalpha/RXRalpha transcriptionally regulate mouse Ostalpha/beta via IR-1 elements shared with FXR/RXRalpha. Exposure to FXR/LXRalpha modulators may affect the disposition of Ostalpha/beta substrates.