ArticleCellular and molecular gastroenterology and hepatology2018
Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter α-β.
Article in Cellular and molecular gastroenterology and hepatology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Structural insights into OSTα/β-mediated transport of bile acids and steroid conjugates.Nature structural & molecular biology · 2026Article
- Impact of Drug-Mediated Inhibition of Intestinal Transporters on Nutrient and Endogenous Substrate Disposition…an Afterthought?Pharmaceutics · 2024Review
- Bile salt signaling and bile salt-based therapies in cardiometabolic disease.Clinical science (London, England : 1979) · 2024Article
- Regulation of bile acids and their receptor FXR in metabolic diseases.Frontiers in nutrition · 2024Review
- Biological tuners to reshape the bile acid pool for therapeutic purposes in non-alcoholic fatty liver disease.Clinical science (London, England : 1979) · 2023Review
- Role of Hepatocyte Transporters in Drug-Induced Liver Injury (DILI)-In Vitro Testing.Pharmaceutics · 2022Review
- Differential and organ-specific functions of organic solute transporter α and β in experimental cholestasis.JHEP reports : innovation in hepatology · 2022Article
- Identification of Key Amino Acids that Impact Organic Solute TransporterMolecular pharmacology · 2021Article
- Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology.Hepatology (Baltimore, Md.) · 2021Review
- Developmental Patterns of Fecal Bile Acids in Healthy Neonates and Children.Medical science monitor : international medical journal of experimental and clinical research · 2021Article
- Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex.Drug delivery · 2020Article
- Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside.Pharmacology & therapeutics · 2020Review
- Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer.International journal of nanomedicine · 2020Article
- Intestinal Absorption of Bile Acids in Health and Disease.Comprehensive Physiology · 2019Review
- Identification of FDA-approved drugs targeting the Farnesoid X Receptor.Scientific reports · 2019Article
- Novel in Vitro Method Reveals Drugs That Inhibit Organic Solute Transporter Alpha/Beta (OSTα/β).Molecular pharmaceutics · 2019Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND &
aimsThe 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.
methodsHere, 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.
resultsAs 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.
conclusionsThis 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.