Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice

Kengo Matsumoto, Mitsunobu Imasato, Yuji Yamazaki, Hiroo Tanaka, Mitsuhiro Watanabe, Hidetoshi Eguchi, Hiroaki Nagano, Hayato Hikita, Tomohide Tatsumi, Tetsuo Takehara, Atsushi Tamura, Sachiko Tsukita

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

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.

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.

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.

Original languageEnglish
Pages (from-to)1134-1145.e10
JournalGastroenterology
Volume147
Issue number5
DOIs
Publication statusPublished - 2014 Nov 1

Fingerprint

Claudin-2
Gallstones
Bile
Cholesterol
Knockout Mice
Hepatocytes
Tight Junctions
Ions
Diet
Bile Ducts
Water
Claudins
Bile Canaliculi
Water Movements
Transcytosis
Aquaporins
Liver
Osmotic Pressure
Cell Adhesion Molecules

Keywords

  • Claudin 2
  • Hepatic Microcirculation
  • Mouse Model
  • TJ

ASJC Scopus subject areas

  • Gastroenterology
  • Medicine(all)

Cite this

Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice. / Matsumoto, Kengo; Imasato, Mitsunobu; Yamazaki, Yuji; Tanaka, Hiroo; Watanabe, Mitsuhiro; Eguchi, Hidetoshi; Nagano, Hiroaki; Hikita, Hayato; Tatsumi, Tomohide; Takehara, Tetsuo; Tamura, Atsushi; Tsukita, Sachiko.

In: Gastroenterology, Vol. 147, No. 5, 01.11.2014, p. 1134-1145.e10.

Research output: Contribution to journalArticle

Matsumoto, K, Imasato, M, Yamazaki, Y, Tanaka, H, Watanabe, M, Eguchi, H, Nagano, H, Hikita, H, Tatsumi, T, Takehara, T, Tamura, A & Tsukita, S 2014, 'Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice', Gastroenterology, vol. 147, no. 5, pp. 1134-1145.e10. https://doi.org/10.1053/j.gastro.2014.07.033
Matsumoto, Kengo ; Imasato, Mitsunobu ; Yamazaki, Yuji ; Tanaka, Hiroo ; Watanabe, Mitsuhiro ; Eguchi, Hidetoshi ; Nagano, Hiroaki ; Hikita, Hayato ; Tatsumi, Tomohide ; Takehara, Tetsuo ; Tamura, Atsushi ; Tsukita, Sachiko. / Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice. In: Gastroenterology. 2014 ; Vol. 147, No. 5. pp. 1134-1145.e10.
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AU - Imasato, Mitsunobu

AU - Yamazaki, Yuji

AU - Tanaka, Hiroo

AU - Watanabe, Mitsuhiro

AU - Eguchi, Hidetoshi

AU - Nagano, Hiroaki

AU - Hikita, Hayato

AU - Tatsumi, Tomohide

AU - Takehara, Tetsuo

AU - Tamura, Atsushi

AU - Tsukita, Sachiko

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N2 - 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.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.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.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.

AB - 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.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.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.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.

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