Approximately 30,000,000 Americans have gallstones, and the vast majority are overweight. This laboratory's long-term objective is to understand the pathogenesis of cholesterol gallstone formation. Gallstone pathogenesis is related to alterations in 1) hepatic lipid metabolism, 2) cholesterol crystal nucleation, and/or 3) biliary motility. Gallstones occur most commonly in obese, middle-aged, multiparous women. Recent studies have clarified the role of gender, iron deficiency, and female hormones in gallstone pathogenesis. Similarly, the role of leptin and malformation of its receptor in the pathogenesis of obesity has been elucidated in the last few years. However, the connections between obesity, leptin and gallstone formation remain obscure. Recent data from this laboratory is congenitally obese ob/ob mice suggest that they have alterations in biliary lipids, enhanced cholesterol crystal formation and increased gallbladder volume. Leptin receptors also have been demonstrated in the liver and biliary tree of both mice and humans. Therefore, the hypothesis of this proposal is that leptin or malfunction of its receptor contribute to the increased incidence of gallstone formation in obesity by altering hepatic lipid metabolism, cholesterol crystal nucleation and biliary motility. Two related specific aims will be 1) to determine whether obesity, leptin, or leptin receptor malfunction alters a) hepatic lipid metabolism, b) cholesterol crystal nucleation, and/or c) biliary motility and 2) determine whether genetic alteration in leptin and its receptor on gallstone formation are additive. Preliminary studies in female, leptin deficient ob/ob mice suggest that these animals are prone to cholesterol gallstone formation. A series of studies in ob/ob, ob+/- (heterozygote), db/db (leptin receptor malfunction, and AY (Agouti yellow) mice as well genetically crossed ob/ob and db/db mice are proposed to dissect which pathogenic mechanisms link obesity, leptin and gallstones. Similarly, bile serum and tissue from lean and obese humans undergoing cholecystectomy will be systematically studied to establish clinical relevance. These studies should lead to unique strategies for gallstone prevention, which is the ultimate goal of this research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK044279-13
Application #
7112033
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Serrano, Jose
Project Start
1992-07-15
Project End
2006-03-31
Budget Start
2004-09-01
Budget End
2005-03-31
Support Year
13
Fiscal Year
2004
Total Cost
$147,574
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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