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A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2012 Jan; Vol. 55 (1), pp. 173-83. - Publication Year :
- 2012
-
Abstract
- Unlabelled: Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized that an apical biliary HCO3- umbrella might prevent the protonation of biliary glycine-conjugated bile salts and uncontrolled cell entry of the corresponding bile acids, and that defects in this biliary HCO3- 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 (1) pH, (2) adequate expression of the key HCO3- exporter, anion exchanger 2 (AE2), and (3) 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 levels. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral short hairpin RNA. 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 the 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.<br />Conclusion: A biliary HCO3- 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 HCO3- umbrella may lead to the development of chronic cholangiopathies.<br /> (Copyright © 2011 American Association for the Study of Liver Diseases.)
- Subjects :
- Anion Transport Proteins genetics
Anion Transport Proteins metabolism
Antiporters genetics
Antiporters metabolism
Apoptosis drug effects
Apoptosis physiology
Bile Duct Neoplasms
Bile Ducts, Intrahepatic cytology
Cell Line, Tumor
Cholangiocarcinoma
Epithelial Cells cytology
Epithelial Cells drug effects
Epithelial Cells metabolism
Extracellular Space metabolism
Gene Knockdown Techniques
Glycocalyx metabolism
Humans
Hydrogen-Ion Concentration drug effects
Microscopy, Electron
Neuraminidase pharmacology
SLC4A Proteins
Bile Acids and Salts pharmacokinetics
Bile Acids and Salts toxicity
Bile Ducts, Intrahepatic drug effects
Bile Ducts, Intrahepatic metabolism
Sodium Bicarbonate pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1527-3350
- Volume :
- 55
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 21932391
- Full Text :
- https://doi.org/10.1002/hep.24691