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

BACKGROUND & AIMS: The organic solute transporter alpha-beta (OST alpha-OST beta) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OST alpha-OST beta 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 OST alpha-OST beta inhibitors have yet been identified. METHODS: Here, we developed a screen to identify specific inhibitors of OST alpha-OST beta using a genetically encoded Forster 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 OST alpha-OST beta and reduced transcellular transport of taurocholate across Madin-Darby canine kidney epithelial cell monolayers expressing apical sodium bile acid transporter and OST alpha-OST beta in a dose-dependent manner. Moreover, pharmacologic inhibition of OST alpha-OST beta 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 OST alpha-OST beta inhibition in vivo. CONCLUSIONS: This study identifies clofazimine as an inhibitor of OST alpha-OST beta in vitro and in vivo, validates OST alpha-OST beta as a drug target to enhance intestinal bile acid signaling, and confirmed the applicability of the Forster Resonance Energy Transfer-bile acid sensor to screen for inhibitors of bile acid efflux pathways.