Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter α-β
| Autor: | Ronald P.J. Oude Elferink, D. Rudi de Waart, Sandra M. W. van de Wiel, Stan F.J. van de Graaf |
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| Přispěvatelé: | Gastroenterology and Hepatology, Graduate School, AGEM - Endocrinology, metabolism and nutrition, Tytgat Institute for Liver and Intestinal Research, AGEM - Digestive immunity, ACS - Atherosclerosis & ischemic syndromes |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MDCKII Madin–Darby canine kidney epithelial cells medicine.drug_class 03 medical and health sciences Bile Acids FXR farnesoid X receptor FACS fluorescence-activated cell sorting medicine nucleoBAS nucleus-localized bile acid sensor lcsh:RC799-869 FRET fluorescent resonance energy transfer TCDCA taurochenodeoxycholic acid Epithelial polarity Original Research U2OS human bone osteosarcoma epithelial cells Hepatology Bile acid OSTα-OSTβ organic solute transporter α-β Chemistry TICE transintestinal cholesterol excretion Gastroenterology Transporter FGF15/19 fibroblast growth factor 15/19 FDA Food and Drug Administration mRNA messenger RNA 3. Good health Cell biology 030104 developmental biology Nuclear receptor Biochemistry FXR FGF15/19 OSTα-OSTβ Paracellular transport Farnesoid X receptor lcsh:Diseases of the digestive system. Gastroenterology Efflux ASBT apical sodium-dependent bile acid transporter Fluorescence Resonance Energy Transfer (FRET) BAS bile acid sensor |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and molecular gastroenterology and hepatology, 5(3), 223-237. Elsevier Inc. Cellular and Molecular Gastroenterology and Hepatology, Vol 5, Iss 3, Pp 223-237 (2018) |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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