Role of Gallbladder Mucus Hypersecretion in the Evolution of Cholesterol Gallstones

Lee, Sum P.; LaMont, J. Thomas; Carey, Martin C.

doi:10.1172/jci110209

Cited by 362 publications

(131 citation statements)

References 47 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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“…Mucin hypersecretion precedes crystal or stone formation. 7,8 These findings suggest that increased mucin secretion plays a role in the initial stages of gallstone formation.We have reported the succesful long-term culturing and passaging of normal, well-differentiated gallbladder epithelial cells from the dog. 9 These cells form electrically leakproof monolayers and synthesize protein and mucous glycoprotein.…”

mentioning

confidence: 95%

“…Mucin hypersecretion precedes crystal or stone formation. 7,8 These findings suggest that increased mucin secretion plays a role in the initial stages of gallstone formation.…”

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confidence: 95%

Lipopolysaccharide From Escherichia Coli Stimulates Mucin Secretion by Cultured Dog Gallbladder Epithelial Cells

et al. 1999

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Biliary infection is associated with mucin hypersecretion by the biliary epithelium. Mucins have been identified as potent pronucleators of cholesterol in bile. The aim of the present study was to determine whether lipopolysaccharides (LPS) from different bacteria are capable of stimulating mucin secretion by cultured dog gallbladder epithelial (DGBE) cells, and to investigate the mechanism by which LPS stimulate mucin secretion. Mucin secretion by confluent monolayers of DGBE cells was quantified by measuring the secretion of [3H]-N-acetyl-D-glucosamine-labeled glycoproteins. Cell viability was evaluated by measuring the leakage of the enzyme, lactate dehydrogenase (LDH), into the culture medium. LPS, derived from Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (200 g/mL), all caused an increase in mucin secretion by the DGBE cells, without causing concomitant cell lysis. LPS from E. coli was found to be the most potent stimulator of mucin secretion, and increased mucin secretion by the DGBE cells to 252% ؎ 14% of control. LPS from E. coli had no effect on intracellular cyclic adenosine monophosphate (cAMP) levels in the DGBE cells. Addition of the nitric oxide (NO)-releasing compound, NOR-4 (0.125-1 mmol/L), to the cells did not result in increased mucin secretion, and the NO synthase inhibitor, N -nitro-L-arginine methyl ester (L-NAME) (4 or 10 mmol/L), did not inhibit the LPSstimulated mucin secretion. Exogenous tumor necrosis factor ␣ (TNF-␣) (1-10 ng/mL) did cause a minor increase in mucin secretion by the DGBE cells, but the effect of LPS from E. coli on mucin secretion could not be inhibited by preincubation with a TNF-␣ antibody (10 g/mL). We conclude that LPS stimulates mucin secretion by the gallbladder epithelium. Whether this stimulation is mediated by TNF-␣ remains to be determined. (HEPATOLOGY 1999;29:1352-1357.)Gallbladder mucin, the primary glycoprotein secreted by the gallbladder, is a densely glycosylated macromolecule with a molecular mass of approximately 2 ϫ 10 6 d. Mucin is regarded as an important contributing factor to gallstone formation. [1][2][3] Mucin has been shown to be present in the nucleus of several types of gallstones, and a macromolecular complex of mucin and bilirubin has been identified as a major structural component of the gallstone matrix. 4,5 Purified human gallbladder mucin is capable of nucleating cholesterol crystals from human bile. 6 Gallbladder mucus hypersecretion and increased mucin concentration are common findings in nearly all animal models of cholesterol gallstone disease. Mucin hypersecretion precedes crystal or stone formation. 7,8 These findings suggest that increased mucin secretion plays a role in the initial stages of gallstone formation.We have reported the succesful long-term culturing and passaging of normal, well-differentiated gallbladder epithelial cells from the dog. 9 These cells form electrically leakproof monolayers and synthesize protein and mucous glycoprotein. They have been extensively studied with regard to water and ...

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“…2,3 Compared with other animals species, [4][5][6] inbred strains of mice allow rigorous genetic control within a strain, yet genetic variance between strains, thereby offering the possibility to dissect the genetics of complex disease pathways. In C57L mice, 2 candidate Lith genes 7 for gallstone susceptibility have been identified on chromosomes 2 and 19.…”

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confidence: 99%

Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi

Fuchs¹,

Ivandic

Müller³

et al. 2001

Hepatology

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Enhanced hepatocellular trafficking of cholesterol to the bile canaliculus and cholesterol hypersecretion appears critical for gallstone formation. Therefore, we studied in more detail the hepatic cholesterol transport pathways in a mouse model of cholesterol gallstone disease. Biliary lipid secretion rates, plasma lipoprotein levels, hepatic expression of lipoprotein receptors, lipid regulatory enzymes, and putative cholesterol transporting proteins were analyzed in gallstone-susceptible C57L/J and gallstone-resistant AKR/J mice, which were fed a lithogenic diet. Biliary cholesterol hypersecretion in C57L mice was associated with decreased plasma high-density lipoprotein (HDL) cholesterol levels and significant hepatic induction of the HDL receptor (SRBI) and cholesteryl ester hydrolase. In response to the lithogenic diet, fatty-acid binding protein of liver (FABPL) was markedly induced in both mouse strains. Caveolin 1 was elevated only in plasma membranes of gallstone-susceptible C57L mice, which also failed to down-regulate cholesterol synthesis. These data suggest a role of the reverse cholesterol transport pathway for genetically determined gallstone susceptibility in the mouse. (HEPATOLOGY 2001;33: 1451-1459.)

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Role of Gallbladder Mucus Hypersecretion in the Evolution of Cholesterol Gallstones

Abstract: A B S T R A C T Because mucin glycoproteins may be important in the pathophysiology of gallstones, we studied the relationship among biliary lipids, gallbladder mucin secretion, and gallstone formation in cholesterol-fed prairie dogs. Organ

Cited by 362 publications

References 47 publications

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

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

Lipopolysaccharide From Escherichia Coli Stimulates Mucin Secretion by Cultured Dog Gallbladder Epithelial Cells

Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi

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