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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