Gallbladder mucin (GMB) plays an important role in gallstone (GS) pathogenesis. Mucin is found within both cholesterol (XOL) and black pigment GS. GBM binds bilirubin, calcium and lipids, and enhances XOL nucleation from supersaturated bile. Hypersecretion of GBM occurs in nearly every animal model of XOL and pigment GS disease. In these animals, XOL crystal growth and stone formation always takes place within the mucin gel and hypersecretion of GBM clearly proceeds stone formation. GS can be prevented simply by inhibiting GBM secretion. This evidence strongly implies that mucin plays a central role in the early steps of GS formation. However, the mechanism(s) by which GBM might potentiate GS development re- main unknown. We hypothesize that hypersecretion of GBM alters normal gallbladder (GB) physiology. This in turn affects the solubility of XOL, calcium and bilirubin in GB bile and within the mucin gel layer leading to GS formation. Mucin is a complex polyanionic macromolecule that lines epithelial surfaces throughout the gastrointestinal tract. In the stomach, mucin plays a major role in the gastric mucosal barrier. Many studies have demonstrated that gastric mucin possesses barrier properties and because of its negative charge can function as a cationic exchanger. As such it can alter electrolyte movement across the epithelial surfaces it covers. In the stomach, these properties protect the gastric mucosa, from a harsh acid environment. In the GB, these same barrier properties might severely, retard electrolyte transport and alter the manner and rate by which the GB modifies bile.
The specific aims of the present study are: 1) to determine if GBM acts as a barrier to the diffusion of electrolytes, bile salts and biliary lipids; 2) to determine if this barrier property alters the ability of the GB to modify GB bile; and 3) to determine if GBM hypersecretion occurs prior to GS formation in man. In vitro studies will be performed to assess the ability of electrolytes, bile salts and lipids to diffuse across a layer of GBM. In vivo studies in the XOL fed prairie dog model will be performed to assess the effects of GBM hypersecretion on the ability of the GB to modify its contents (ie. concentrate and acidify bile and reabsorb biliary lipids). GB bile will also be collected from persons undergoing gastric surgery as treatment for morbid obesity. Approximately 36% of these patients develop GS during rapid weight loss. In these patients GB bile composition and GBM content can be assessed prior to GS formation. The development of polyclonal antibodies against human GBM will facilitate and simplify measurements of this substance. This 3-faceted approach will provide important insight into the role of GBM in GS pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK043264-02
Application #
3464337
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1991-08-05
Project End
1996-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Sterling, R K; Shiffman, M L; Sugerman, H J et al. (1995) Effect of NSAIDs on gallbladder bile composition. Dig Dis Sci 40:2220-6
Shiffman, M L; Kaplan, G D; Brinkman-Kaplan, V et al. (1995) Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med 122:899-905
Shiffman, M L; Shamburek, R D; Schwartz, C C et al. (1993) Gallbladder mucin, arachidonic acid, and bile lipids in patients who develop gallstones during weight reduction. Gastroenterology 105:1200-8
Shiffman, M L; Sugerman, H J; Kellum, J H et al. (1993) Gallstones in patients with morbid obesity. Relationship to body weight, weight loss and gallbladder bile cholesterol solubility. Int J Obes Relat Metab Disord 17:153-8
Shiffman, M L; Sugerman, H J; Kellum, J M et al. (1992) Calcium in human gallbladder bile. J Lab Clin Med 120:875-84
Shiffman, M L; Sugerman, H J; Kellum, J M et al. (1992) Changes in gallbladder bile composition following gallstone formation and weight reduction. Gastroenterology 103:214-21