Abstract
Gallbladder mucins play a critical role in the pathogenesis of cholesterol gallstones because of their ability to bind biliary lipids and accelerate cholesterol crystallization. Mucin secretion and accumulation in the gallbladder is determined by multiple mucin genes. To study whether mucin gene 1 (Muc1) influences susceptibility to cholesterol cholelithiasis, we investigated male Muc1-deficient (Muc1(-/-)) and wild-type mice fed a lithogenic diet containing 1% cholesterol and 0.5% cholic acid for 56 days. Gene expression of the gallbladder Muc1 and Muc5ac was significantly reduced in Muc1(-/-) mice in response to the lithogenic diet. Muc3 and Muc4 levels were upregulated and were similar between Muc1(-/-) and wild-type mice. Little or no Muc2 and Muc5b mRNAs were detected. Muc1(-/-) mice displayed significant decreases in total mucin secretion and accumulation in the gallbladder as well as retardation of crystallization, growth, and agglomeration of cholesterol monohydrate crystals. At 56 days of feeding, gallstone prevalence was decreased by 40% in Muc1(-/-) mice. However, cholesterol saturation indices of gallbladder bile, hepatic secretion of biliary lipids, and gallbladder size were comparable in Muc1(-/-) and wild-type mice. We conclude that decreased gallstone formation in mice with disrupted Muc1 gene results from reduced mucin secretion and accumulation in the gallbladder.
Highlights
Gallbladder mucins play a critical role in the pathogenesis of cholesterol gallstones because of their ability to bind biliary lipids and accelerate cholesterol crystallization
Our results show that targeted disruption of the mucin gene 1 (Muc1) gene significantly decreases mucin secretion and accumulation in the gallbladder of Muc1Ϫ/Ϫ mice compared with wild-type mice
The most important findings are that i) targeted disruption of the murine Muc1 gene significantly decreases susceptibility to cholesterol gallstone formation by reducing gallbladder mucin secretion and accumulation, leading to the retardation of crystallization, growth, and agglomeration of cholesterol monohydrate crystals in biles as well as the development of gallstones; ii) appearance times of cholesterol monohydrate crystals are significantly decelerated and numbers of solid cholesterol crystals are significantly smaller in model biles with the addition of mucin gel purified from gallbladder biles of Muc1Ϫ/Ϫ mice; and iii) knockout of the Muc1 gene influences neither cholesterol saturation indices of gallblad
Summary
Gallbladder mucins play a critical role in the pathogenesis of cholesterol gallstones because of their ability to bind biliary lipids and accelerate cholesterol crystallization. To study whether mucin gene 1 (Muc1) influences susceptibility to cholesterol cholelithiasis, we investigated male Muc1-deficient (Muc1؊/؊) and wild-type mice fed a lithogenic diet containing 1% cholesterol and 0.5% cholic acid for 56 days. Cholesterol saturation indices of gallbladder biles, hepatic secretion of biliary lipids, and gallbladder size were comparable in Muc1؊/؊ and wild-type mice. We conclude that decreased gallstone formation in mice with disrupted Muc gene results from reduced mucin secretion and accumulation in the gallbladder.—Wang, H. The gel-forming mucins, Muc, Muc5ac, and Muc5b, secreted by specialized gallbladder mucin-producing cells provide a protective coating to the underlying mucosa. They form disulfide-stabilized oligomers or polymers, a phenomenon that accounts for their viscoelastic properties. Spicer and coworkers [17] found that mice deficient in Muc mucin appear to develop normally and are healthy and fertile, Abbreviations: CCK, cholecystokinin; Muc, mucin gene 1. 1 This paper was presented in part at the Annual Meeting of the American Gastroenterological Association, Orlando, FL, in 2003, and published as an abstract in Gastroenterology. 2003. 124: A698. 2 To whom correspondence should be addressed
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