Publications (2018-2020)

Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter a-b.

Sandra M. W. van de Wiel, D. Rudi de Waart, Ronald P. J. Oude Elferink, and S. F. J. van de G.
Cell Mol Gastroenterol Hepatol 5 223–237 (2018)

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.


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.


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.


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.

Keywords: Fluorescence Resonance Energy Transfer (FRET), FXR, OSTα-OSTβ, Bile Acids
Abbreviations used in this paper: ASBT, apical sodium-dependent bile acid transporter; BAS, bile acid sensor; FACS, fluorescence-activated cell sorting; FDA, Food and Drug Administration; FGF15/19, fibroblast growth factor 15/19; FRET, fluorescent resonance energy transfer; FXR, farnesoid X receptor; MDCKII, Madin–Darby canine kidney epithelial cells; mRNA, messenger RNA; nucleoBAS, nucleus-localized bile acid sensor; OSTα-OSTβ, organic solute transporter α-β; TCDCA, taurochenodeoxycholic acid; TICE, transintestinal cholesterol excretion; U2OS, human bone osteosarcoma epithelial cells
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