Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter α-β

BACKGROUND & AIMS: The organic solute transporter α-β (OSTα-OSTβ) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OSTα-OSTβ might have similar beneficial metabolic effects as intestine-specific agonists of the major nuclear receptor for bile acids, the farnesoid X receptor (FXR). However, no OSTα-OSTβ inhibitors have yet been identified. METHODS: Here, we developed a screen to identify specific inhibitors of OSTα-OSTβ using a genetically encoded Förster Resonance Energy Transfer (FRET)–bile acid sensor that enables rapid visualization of bile acid efflux in living cells. RESULTS: As proof of concept, we screened 1280 Food and Drug Administration–approved drugs of the Prestwick chemical library. Clofazimine was the most specific hit for OSTα-OSTβ and reduced transcellular transport of taurocholate across Madin–Darby canine kidney epithelial cell monolayers expressing apical sodium bile acid transporter and OSTα-OSTβ in a dose-dependent manner. Moreover, pharmacologic inhibition of OSTα-OSTβ also moderately increased intracellular taurocholate levels and increased activation of intestinal FXR target genes. Oral administration of clofazimine in mice (transiently) increased intestinal FXR target gene expression, confirming OSTα-OSTβ inhibition in vivo. CONCLUSIONS: This study identifies clofazimine as an inhibitor of OSTα-OSTβ in vitro and in vivo, validates OSTα-OSTβ as a drug target to enhance intestinal bile acid signaling, and confirmed the applicability of the Förster Resonance Energy Transfer–bile acid sensor to screen for inhibitors of bile acid efflux pathways.