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

Helen H. Wang, Nezam H. Afdhal, Sandra J. Gendler, David Q.H. Wang

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)438-447
Number of pages10
JournalJournal of Lipid Research
Volume45
Issue number3
DOIs
StatePublished - Mar 1 2004
Externally publishedYes

Fingerprint

Mucin-1
Gallstones
Mucins
Genes
Cholesterol
Gallbladder
Crystallization
Nutrition
Diet
Lipids
Cholic Acid
Cholelithiasis
Bile
Gene expression

Keywords

  • Bile
  • Bile flow
  • Bile salt
  • Biliary cholesterol secretion
  • Crystallization
  • Liquid crystals
  • Microscopy
  • Mucin gel
  • Mucoprotein surface coat

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Targeted disruption of the murine mucin gene 1 decreases susceptibility to cholesterol gallstone formation. / Wang, Helen H.; Afdhal, Nezam H.; Gendler, Sandra J.; Wang, David Q.H.

In: Journal of Lipid Research, Vol. 45, No. 3, 01.03.2004, p. 438-447.

Research output: Contribution to journalArticle

Wang, Helen H. ; Afdhal, Nezam H. ; Gendler, Sandra J. ; Wang, David Q.H. / Targeted disruption of the murine mucin gene 1 decreases susceptibility to cholesterol gallstone formation. In: Journal of Lipid Research. 2004 ; Vol. 45, No. 3. pp. 438-447.
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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 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.",
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