title: Clinical application of transcriptional activators of bile salt transporters.
abstract: Hepatobiliary bile salt (BS) transporters are critical determinants of BS homeostasis controlling intracellular concentrations of BSs and their enterohepatic circulation. Genetic or acquired dysfunction of specific transport systems causes intrahepatic and systemic retention of potentially cytotoxic BSs, which, in high concentrations, may disturb integrity of cell membranes and subcellular organelles resulting in cell death, inflammation and fibrosis. Transcriptional regulation of canalicular BS efflux through bile salt export pump (BSEP), basolateral elimination through organic solute transporters alpha and beta (OSTα/OSTβ) as well as inhibition of hepatocellular BS uptake through basolateral Na(+)-taurocholate cotransporting polypeptide (NTCP) represent critical steps in protection from hepatocellular BS overload and can be targeted therapeutically. In this article, we review the potential clinical implications of the major BS transporters BSEP, OSTα/OSTβ and NTCP in the pathogenesis of hereditary and acquired cholestatic syndromes, provide an overview on transcriptional control of these transporters by the key regulatory nuclear receptors and discuss the potential therapeutic role of novel transcriptional activators of BS transporters in cholestasis.
authors: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.
authors: Anna
authors: A
authors: Baghdasaryan
authors: Institute of Medical Chemistry, Medical University of Vienna, Austria.
authors: Peter
authors: P
authors: Chiba
authors: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.
authors: Michael
authors: M
authors: Trauner
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D002779:Cholestasis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005786:Gene Expression Regulation; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C476575:organic solute transporter alpha, human; C476577:SLC51B protein, human; C071908:sodium-bile acid cotransporter
keywords: 24-norUDCA (PubChem CID: 192254); ATB-binding cassette transporters; Bezafibrate (PubChem CID: 39042); Budesonide (PubChem CID: 5281004); Cholestasis; FXR-450/WAY-362450 (PubChem CID: 10026128); Fenofibrate (PubChem CID: 3339); GW4064 (PubChem CID: 9893571); Nuclear receptors; Obeticholic acid/INT-747/6alpha-ethylchenodeoxycholic acid (PubChem CID: 447715); Phenobarbital (PubChem CID: 4763); Rifampicin (PubChem CID: 5381226); Ursodeoxycholic acid/UDCA/ursodiol (PubChem CID: 31401)