| A biliary HCO(3) (-) umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. | |
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MedLine Citation:
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PMID: 21932391 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized, that an apical biliary HCO(3) (-) umbrella might prevent protonation of biliary glycine-conjugated bile salts and uncontrolled cell entry of the corresponding bile acids and that defects in this biliary HCO(3) (-) umbrella might predispose to chronic cholangiopathies. Here, we tested in vitro whether human cholangiocyte integrity in the presence of millimolar bile salt monomers is dependent on (i) pH, (ii) adequate expression of the key HCO(3) (-) exporter, anion exchanger 2 (AE2), and (iii) an intact cholangiocyte glycocalyx. To address these questions, human immortalized cholangiocytes and cholangiocarcinoma cells were exposed to chenodeoxycholate and its glycine/taurine conjugates at different pH. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral shRNA. A cholangiocyte glycocalyx was identified by electron microscopy, was enzymatically desialylated, and sialylation was quantified by flow cytometry. We found that bile acid uptake and toxicity in human immortalized cholangiocytes and cholangiocarcinoma cell lines in vitro were pH- and AE2-dependent with highest rates at low pH and when AE2 expression was defective. An apical glycocalyx was identified on cholangiocytes in vitro by electron microscopic techniques. Desialylation of this protective layer increased cholangiocellular vulnerability in a pH-dependent manner. CONCLUSION: A biliary HCO(3) (-) umbrella protects human cholangiocytes against damage by bile acid monomers. An intact glycocalyx and adequate AE2 expression are crucial in this process. Defects of the biliary HCO(3) (-) umbrella may lead to development of chronic cholangiopathies. (HEPATOLOGY 2011.). |
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Authors:
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Simon Hohenester; Lucas Maillette de Buy Wenniger; Coen C Paulusma; Sandra J van Vliet; Douglas M Jefferson; Ronald P Oude Elferink; Ulrich Beuers |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-19 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Association for the Study of Liver Diseases. |
Affiliation:
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Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine III, University of Aachen, Aachen, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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