Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter α-ß.
Cell Mol Gastroenterol Hepatol
; 5(3): 223-237, 2018 Mar.
Article
en En
| MEDLINE
| ID: mdl-29675448
ABSTRACT
BACKGROUND & AIMS:
The organic solute transporter α-ß (OSTα-OSTß) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OSTα-OSTß 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-OSTß inhibitors have yet been identified.METHODS:
Here, we developed a screen to identify specific inhibitors of OSTα-OSTß 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-OSTß and reduced transcellular transport of taurocholate across Madin-Darby canine kidney epithelial cell monolayers expressing apical sodium bile acid transporter and OSTα-OSTß in a dose-dependent manner. Moreover, pharmacologic inhibition of OSTα-OSTß 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-OSTß inhibition in vivo.CONCLUSIONS:
This study identifies clofazimine as an inhibitor of OSTα-OSTß in vitro and in vivo, validates OSTα-OSTß 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.
ASBT, apical sodium-dependent bile acid transporter; BAS, bile acid sensor; Bile Acids; FACS, fluorescence-activated cell sorting; FDA, Food and Drug Administration; FGF15/19, fibroblast growth factor 15/19; FRET, fluorescent resonance energy transfer; FXR; FXR, farnesoid X receptor; Fluorescence Resonance Energy Transfer (FRET); MDCKII, MadinDarby canine kidney epithelial cells; OSTα-OSTß; OSTα-OSTß, organic solute transporter α-ß; TCDCA, taurochenodeoxycholic acid; TICE, transintestinal cholesterol excretion; U2OS, human bone osteosarcoma epithelial cells; mRNA, messenger RNA; nucleoBAS, nucleus-localized bile acid sensor
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cell Mol Gastroenterol Hepatol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Países Bajos