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Journal of Lipid Research, Vol. 45, 438-447, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Targeted disruption of the murine mucin gene 1 decreases susceptibility to cholesterol gallstone formation¹

Helen H. Wang^*, Nezam H. Afdhal^*, Sandra J. Gendler and David Q-H. Wang^2,*

^* Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, and Harvard Digestive Diseases Center, Boston, MA 02215
Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, AZ 85259

² To whom correspondence should be addressed. e-mail: 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 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 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.

Abbreviations: CCK, cholecystokinin; Muc1, mucin gene 1

Supplementary key words bile • bile flow • bile salt • biliary cholesterol secretion • crystallization • liquid crystals • microscopy • mucoprotein surface coat • mucin gel

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