Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice
Author(s): ,
Sachiko Tsukita
Affiliations:
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
Corresponding authors. Address: Graduate School of Frontier Biosciences and of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Tel.: +81-6-6879-3320; fax: +81-6-6879-3329 (S. Tsukita).
,
Atsushi Tamura
Affiliations:
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
Corresponding authors. Address: Graduate School of Frontier Biosciences and of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Tel.: +81-6-6879-3320; fax: +81-6-6879-3329 (S. Tsukita).
,
Mitsuhiro Watanabe
Affiliations:
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
,
Naho Kitamura
Affiliations:
Graduate School of Media and Governance, Faculty of Environment Information Studies, Keio University, Kanagawa, Japan
,
Marino Zerial
Affiliations:
Center for Advancing Electronics Dresden, Technische Universitat Dresden, Dresden, Germany
,
Kirstin Meyer
Affiliations:
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
,
Julien Delpierre
Affiliations:
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
,
Koshi Kunimoto
Affiliations:
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
,
Kengo Matsumoto
Affiliations:
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
,
Yuji Yamazaki
Affiliations:
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
,
Mitsunobu Imasato
Affiliations:
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
Hiroo Tanaka
Affiliations:
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
EASL LiverTree™. Tsukita S. Dec 1, 2018; 256740
Sachiko Tsukita
Sachiko Tsukita
Contributions
Journal Abstract
References
Graphical abstract

Graphical abstract

Hepatic claudin-3 (Cldn3) expression decreases with aging in mice. Cldn3 deficiency causes dysfunction in the paracellular barrier for phosphate ions. Dysfunctional biliary metabolism of phosphate ions induces calcium phosphate core formation. A calcium phosphate core induces cholesterol gallstone formation.

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.

Keyword(s)
Epithelial Barrier, Tight junction, Claudin, Paracellular permeability, Phosphate ion, Phosphate gallstone, Cholesterol gallstone
[1]. K.S. Gurusamy - Gallstones
[2]. F. Lammert - Gallstones
[3]. T. Qiao - The systematic classification of gallbladder stones
[4]. H. Weerakoon - Chemical characterization of gallstones: an approach to explore the aetiopathogenesis of gallstone disease in Sri Lanka
[5]. H.S. Kaufman - The distribution of calcium salt precipitates in the core, periphery and shell of cholesterol, black pigment and brown pigment gallstones
[6]. E.W. Moore - The role of calcium in the pathogenesis of gallstones: Ca++ electrode studies of model bile salt solutions and other biologic systems. With an hypothesis on structural requirements for Ca++ binding to proteins and bile acids
[7]. S.B. Biddinger - Hepatic insulin resistance directly promotes formation of cholesterol gallstones
[8]. S. Buch - A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease
[9]. J. He - PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts
[10]. G.M. Hirschfield - The genetics of complex cholestatic disorders
[11]. A.D. Joshi - Four susceptibility loci for gallstone disease identified in a meta-analysis of genome-wide association studies
[12]. A. Moschetta - Prevention of cholesterol gallstone disease by FXR agonists in a mouse model
[13]. V. Valdivieso - Effect of aging on biliary lipid composition and bile acid metabolism in normal Chilean women
[14]. M.S. Calvo - Assessing the health impact of phosphorus in the food supply: issues and considerations
[15]. Y. Asai - Activation of the hypoxia inducible factor 1alpha subunit pathway in steatotic liver contributes to formation of cholesterol gallstones
[16]. J.L. Boyer - Bile formation and secretion
[17]. K. Meyer - A predictive 3D multi-scale model of biliary fluid dynamics in the liver lobule
[18]. W.W. Franke - Discovering the molecular components of intercellular junctions-a historical view
[19]. C. Zihni - Tight junctions: from simple barriers to multifunctional molecular gates
[20]. K. Mineta - Predicted expansion of the claudin multigene family
[21]. Y. Saitoh - Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin
[22]. H. Suzuki - Crystal structure of a claudin provides insight into the architecture of tight junctions
[23]. H. Suzuki - Model for the architecture of claudin-based paracellular ion channels through tight junctions
[24]. C. Rahner - Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut
[25]. K. Matsumoto - Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice
[26]. R. Rosenthal - Claudin-2, a component of the tight junction, forms a paracellular water channel
[27]. C.R. Weber - Claudin-2-dependent paracellular channels are dynamically gated
[28]. L. Pei - Paracellular epithelial sodium transport maximizes energy efficiency in the kidney
[29]. R. Rosenthal - Water channels and barriers formed by claudins
[30]. P.Y. Tsai - IL-22 upregulates epithelial claudin-2 to drive diarrhea and enteric pathogen clearance
[31]. H. Tanaka - Site-specific distribution of claudin-based paracellular channels with roles in biological fluid flow and metabolism
[32]. L.A. Perez Jurado - Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth
[33]. U. Francke - Williams-Beuren syndrome: genes and mechanisms
[34]. B. Barak - Neurobiology of social behavior abnormalities in autism and Williams syndrome
[35]. A. Giannotti - Coeliac disease in Williams syndrome
[36]. T. D'Souza - Age-related changes of claudin expression in mouse liver, kidney, and pancreas
[37]. H. Tanaka - Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice
[38]. M. Watanabe - Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure
[39]. M. Watanabe - Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c
[40]. P. Portincasa - Water channel proteins in bile formation and flow in health and disease: when immiscible becomes miscible
[41]. K. Miyamoto - Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies
[42]. M.D. Berman - Metastable and equilibrium phase diagrams of unconjugated bilirubin IXalpha as functions of pH in model bile systems: implications for pigment gallstone formation
[43]. A.R. Concepcion - Role of AE2 for pHi regulation in biliary epithelial cells
[44]. S. Tsukita - Multifunctional strands in tight junctions
[45]. S. Milatz - Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes

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