Evidence That Gallbladder Epithelial Mucin Enhances Cholesterol Cholelithogenesis in MUC1 Transgenic Mice

Abstract

The gel-forming mucins play an important role in the early stage of cholesterol gallstone formation. We investigated whether the gallbladder epithelial mucin encoded by mucin gene 1 (MUC1) influences susceptibility to gallstones. Gallbladder motility and cholesterol absorption, gallstones and expression of the mucin genes in gallbladders, and secretion rates and compositions of biliary lipids were determined in male C57BL/6J mice transgenic for the human MUC1 gene (MUC1.Tg) and wild-type mice before (day 0, on chow) and at 4 weeks on a lithogenic diet containing 1% cholesterol and 0.5% cholic acid. On chow, expression levels of the gallbladder mucin genes were essentially similar between MUC1.Tg and wild-type mice. The lithogenic diet induced 3-fold higher expression levels of Muc1, Muc3, Muc4, Muc5ac, and Muc5b messenger RNA in MUC1.Tg mice compared with wild-type mice. Gallbladder cholesterol absorption and size were significantly greater in MUC1.Tg mice than in wild-type mice regardless of whether the chow or the lithogenic diet was fed. Gallbladder emptying in response to exogenously administered cholecystokinin-8 was significantly reduced in MUC1.Tg mice but not in wild-type mice. At 4 weeks on the lithogenic diet, mucin accumulation was found in all MUC1Tg mice and in 60% of wild-type mice. Consequently, these alterations greatly accelerated cholesterol crystallization and gallstone formation in MUC1.Tg mice. However, biliary lipid secretion rates and cholesterol saturation indices of gallbladder biles were comparable in MUC1.Tg and wild-type mice. Increased gallbladder epithelial MUC1 mucin enhances cholelithogenesis by promoting gallbladder cholesterol absorption and impairing gallbladder motility in mice.