Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice

Hiroo Tanaka, Mitsunobu Imasato, Yuji Yamazaki, Kengo Matsumoto, Koshi Kunimoto, Julien Delpierre, Kirstin Meyer, Marino Zerial, Naho Kitamura, Mitsuhiro Watanabe, Atsushi Tamura, Sachiko Tsukita

Research output: Contribution to journalArticle

11 Citations (Scopus)

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. 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. 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. 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. 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.

Original languageEnglish
Pages (from-to)1308-1316
Number of pages9
JournalJournal of Hepatology
Volume69
Issue number6
DOIs
Publication statusPublished - 2018 Dec

Keywords

  • Cholesterol gallstone
  • Claudin
  • Epithelial Barrier
  • Paracellular permeability
  • Phosphate gallstone
  • Phosphate ion
  • Tight junction

ASJC Scopus subject areas

  • Hepatology

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    Tanaka, H., Imasato, M., Yamazaki, Y., Matsumoto, K., Kunimoto, K., Delpierre, J., Meyer, K., Zerial, M., Kitamura, N., Watanabe, M., Tamura, A., & Tsukita, S. (2018). Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice. Journal of Hepatology, 69(6), 1308-1316. https://doi.org/10.1016/j.jhep.2018.08.025