1 research outputs found
Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter Ī±-Ī²
The organic solute transporter Ī±-Ī² (OSTĪ±-OSTĪ²) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OSTĪ±-OSTĪ² 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 OSTĪ±-OSTĪ² inhibitors have yet been identified.
Methods: Here, we developed a screen to identify specific inhibitors of OSTĪ±-OSTĪ² using a genetically encoded Fƶrster Resonance Energy Transfer (FRET)ābile acid sensor that enables rapid visualization of bile acid efflux in living cells.
Results: As proof of concept, we screened 1280 Food and Drug Administrationāapproved drugs of the Prestwick chemical library. Clofazimine was the most specific hit for OSTĪ±-OSTĪ² and reduced transcellular transport of taurocholate across MadināDarby canine kidney epithelial cell monolayers expressing apical sodium bile acid transporter and OSTĪ±-OSTĪ² in a dose-dependent manner. Moreover, pharmacologic inhibition of OSTĪ±-OSTĪ² 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 OSTĪ±-OSTĪ² inhibition inĀ vivo.
Conclusions: This study identifies clofazimine as an inhibitor of OSTĪ±-OSTĪ² inĀ vitro and inĀ vivo, validates OSTĪ±-OSTĪ² as a drug target to enhance intestinal bile acid signaling, and confirmed the applicability of the Fƶrster Resonance EnergyĀ Transferābile acid sensor to screen for inhibitors of bile acid efflux pathways