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Papers In Press, published online ahead of print January 1, 2004
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Department of Medicine, Gastroenterology Division, Beth Israel Deaconess Medical Center, Boston, MA 02215
Corresponding Author: dqwang{at}caregroup.harvard.edu
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 up-regulated and were similar between Muc1-/- and wild-type mice. Little to 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 the feeding, gallstone prevalence was decreased by 40% in Muc1-/- mice. However, 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 Muc1 gene results from reduced mucin secretion and accumulation in the gallbladder.
Revised on December 19, 2003
Accepted on December 19, 2003
Targeted disruption of the murine mucin gene 1 decreases susceptibility to cholesterol gallstone formation
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