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Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice.
- Source :
-
Gastroenterology [Gastroenterology] 2014 Nov; Vol. 147 (5), pp. 1134-45.e10. Date of Electronic Publication: 2014 Jul 25. - Publication Year :
- 2014
-
Abstract
- Background & Aims: Bile formation and secretion are essential functions of the hepatobiliary system. Bile flow is generated by transepithelial transport of water and ionic/nonionic solutes via transcellular and paracellular pathways that is mainly driven by osmotic pressure. We examined the role of tight junction-based paracellular transport in bile secretion. Claudins are cell-cell adhesion molecules in tight junctions that create the paracellular barrier. The claudin family has 27 reported members, some of which have paracellular ion- and/or water-channel-like functions. Claudin 2 is a paracellular channel-forming protein that is highly expressed in hepatocytes and cholangiocytes; we examined the hepatobiliary system of claudin 2 knockout (Cldn2(-/-)) mice.<br />Methods: We collected liver and biliary tissues from Cldn2(-/-) and Cldn2(+/+) mice and performed histologic, biochemical, and electrophysiologic analyses. We measured osmotic movement of water and/or ions in Cldn2(-/-) and Cldn2(+/+) hepatocytes and bile ducts. Mice were placed on lithogenic diets for 4 weeks and development of gallstone disease was assessed.<br />Results: The rate of bile flow in Cldn2(-/-) mice was half that of Cldn2(+/+) mice, resulting in significantly more concentrated bile in livers of Cldn2(-/-) mice. Consistent with these findings, osmotic gradient-driven water flow was significantly reduced in hepatocyte bile canaliculi and bile ducts isolated from Cldn2(-/-) mice, compared with Cldn2(+/+) mice. After 4 weeks on lithogenic diets, all Cldn2(-/-) mice developed macroscopically visible gallstones; the main component of the gallstones was cholesterol (>98%). In contrast, none of the Cldn2(+/+) mice placed on lithogenic diets developed gallstones.<br />Conclusions: Based on studies of Cldn2(-/-) mice, claudin 2 regulates paracellular ion and water flow required for proper regulation of bile composition and flow. Dysregulation of this process increases susceptibility to cholesterol gallstone disease in mice.<br /> (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Aged
Animals
Case-Control Studies
Cells, Cultured
Claudins genetics
Claudins metabolism
Disease Models, Animal
Epithelial Cells metabolism
Epithelial Cells pathology
Female
Gallbladder pathology
Gallstones genetics
Gallstones pathology
Humans
Liver pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Osmotic Pressure
Permeability
Tight Junctions pathology
Time Factors
Water metabolism
Bile metabolism
Cholesterol metabolism
Claudins deficiency
Gallbladder metabolism
Gallstones metabolism
Liver metabolism
Tight Junctions metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 147
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 25068494
- Full Text :
- https://doi.org/10.1053/j.gastro.2014.07.033