Aspirin Prevention of Cholesterol Gallstone Formation in Prairie Dogs

Sp, Lee; Mc, Carey; LaMont, J. Thomas

doi:10.1126/science.7466399

Cited by 234 publications

(67 citation statements)

References 36 publications

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“…In addition to these protective functions, several lines of evidence have shown that gall bladder mucin plays an integral role in the pathogenesis of cholesterol gallstone disease. First, hypersecretion of gall bladder mucin precedes gallstone formation in cholesterol-fed prairie dogs [5] and inhibition of mucin secretion with aspirin prevents stone formation [6]. Secondly, purified human gall bladder mucin accelerates the nucleation of cholesterol crystals in itro in a time-and concentration-dependent manner [7], and thirdly, the presence of mucin within cholesterol gallstones has been demonstrated by electron-microscopic and biochemical techniques [8,9].…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning of a major human gall bladder mucin: complete C-terminal sequence and genomic organization of MUC5B

Keates

Nunes

Afdhal

et al. 1997

Biochemical Journal

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Gall bladder mucin has been shown to play a central role in the pathogenesis of cholesterol gallstone disease. While cloning and sequencing studies have provided a wealth of information on the structure of other gastrointestinal and respiratory mucins, nothing is known about the primary structure of human gall bladder mucin. In this study, we show that the tracheobronchial mucin MUC5B is a major mucin gene product expressed in the gall bladder. Antibodies directed against deglycosylated human gall bladder mucin were used to screen a gall bladder cDNA expression library, and most of the isolated clones contained repetitive sequences nearly identical with those in the tandem repeat region of MUC5B. An additional clone (hGBM2-3) contained an open reading frame coding for a 389 residue cysteine-rich sequence. The arrangement of cysteine residues in this sequence was very similar to that in the C-terminal regions of MUC2, MUC5AC and human von Willebrand factor. This cysteine-rich sequence was connected to a series of degenerate MUC5B tandem repeats in a 7.5 kb HincII genomic DNA fragment. This fragment, with ten exons and nine introns, contained MUC5B repeats in exon 1 and a 469 residue cysteine-rich sequence in exons 2–10 that provided a 152 nucleotide overlap with cDNA clone hGBM2-3. Interestingly, the exon–intron junctions in the MUC5B genomic fragment occurred at positions equivalent to those in the D4 domain of human von Willebrand factor, suggesting that these proteins evolved from a common evolutionary ancestor through addition or deletion of exons encoding functional domains.

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Section: Introductionmentioning

confidence: 99%

Molecular cloning of a major human gall bladder mucin: complete C-terminal sequence and genomic organization of MUC5B

Keates

Nunes

Afdhal

et al. 1997

Biochemical Journal

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“…Decreasing MUC secretion with aspirin prevents gallstone formation in animal models and decreases the risk of gallstone recurrence following dissolution therapy in humans. 91,92 New progress has been made to identify the initiating event that triggers the observed MUC hypersecretion in recent years. A shift in the bile salt composition toward more hydrophobic, as occurs in lithogenic bile, is more effective at stimulating MUC secretion.…”

Section: Cholesterol Nucleation Promoting and Inhibiting Proteinsmentioning

confidence: 99%

Cholesterol gallstone disease: focusing on the role of gallbladder

Chen

Kong

2015

Laboratory Investigation

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Gallstone disease (GSD) is one of the most common biliary tract diseases worldwide in which both genetic and environmental factors have roles in its pathogenesis. Biliary cholesterol supersaturation from metabolic defects in the liver is traditionally seen as the main pathogenic factor. Recently, there have been renewed investigative interests in the downstream events that occur in gallbladder lithogenesis. This article focuses on the role of the gallbladder in the pathogenesis of cholesterol GSD (CGD). Various conditions affecting the crystallization process are discussed, such as gallbladder motility, concentrating function, lipid transport, and an imbalance between pro-nucleating and nucleation inhibiting proteins.

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“…Aspirin has been found to reduce mucin gel production in cholesterol-fed prairie dog gall bladder and to inhibit gallstone formation by acting on the mucosal factors of gallstones formation [13]. Aspirin alone does not seem to reduce the prevalence of gallstones disease in a population of regular aspirin users [16] but it can prevent the recurrence of gallstones after oral bile acid dissolution and can reduce gallstone incidence (at a dose of 1000 mg/day orally) in obese patients undergoing rapid body weight loss [16].…”

Section: Expert Opinionmentioning

confidence: 99%

“…The added cholesterol promotes mucin synthesis and secretion in the gall bladder lumen; cholesterol gallstone nucleation from cholesterol monohydrate crystals is observed in the mucus adherent to the gall bladder epithelium, but not in the bulk lumen. Aspirin administered simultaneously in cholesterol-fed prairie dog causes a dose-dependent inhibition of mucin secretion by the gall bladder epithelium and prevents cholesterol monohydrate crystal nucleation and cholesterol gallstone formation also in a cholesterol supersaturated bile [13].…”

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confidence: 99%