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Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice.
- Source :
-
Journal of hepatology [J Hepatol] 2018 Dec; Vol. 69 (6), pp. 1308-1316. Date of Electronic Publication: 2018 Sep 11. - Publication Year :
- 2018
-
Abstract
- Background & Aims: Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstones, with particular interest in the role of phosphate ion, a common food additive and preservative.<br />Methods: We focused on claudin-3 (Cldn3), a paracellular barrier-forming tight junction protein whose expression in mouse liver decreases with age. Since Cldn3-knockout mice exhibited gallstone diseases, we used them to assess the causal relationship between paracellular phosphate ion permeability and the core formation of cholesterol gallstones.<br />Results: In the liver of Cldn3-knockout mice, the paracellular phosphate ion permeability through hepatic tight junctions was significantly increased, resulting in calcium phosphate core formation. Cholesterol overdose caused cholesterol gallstone disease in these mice.<br />Conclusion: We revealed that in the hepatobiliary system, Cldn3 functions as a paracellular barrier for phosphate ions, to help maintain biliary ion homeostasis. We provide in vivo evidence that elevated phosphate ion concentrations play a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease under cholesterol overdose.<br />Lay Summary: Herein, we reveal a new mechanism for cholesterol gallstone formation, in which increased paracellular phosphate ion permeability across hepatobiliary epithelia causes calcium phosphate core formation and cholesterol gallstones. Thus, altered phosphate ion metabolism under cholesterol overdose plays a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease.<br /> (Copyright © 2018. Published by Elsevier B.V.)
- Subjects :
- Aging physiology
Animals
Aquaporins metabolism
Calcium metabolism
Calcium Phosphates metabolism
Claudin-3 genetics
Claudins genetics
Claudins metabolism
Female
Gene Knockout Techniques
Liver metabolism
Male
Mice
Mice, Knockout
Phosphorus metabolism
Tight Junctions metabolism
Bile Canaliculi metabolism
Cell Membrane Permeability physiology
Cholesterol metabolism
Claudin-3 metabolism
Gallstones metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0641
- Volume :
- 69
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 30213590
- Full Text :
- https://doi.org/10.1016/j.jhep.2018.08.025