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 #
5R01DK044279-11
Application #
6634987
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Serrano, Jose
Project Start
1992-07-15
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
11
Fiscal Year
2003
Total Cost
$281,963
Indirect Cost
Name
Medical College of Wisconsin
Department
Surgery
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Parikh, Janak Atul; Beane, Joal D; Kilbane, E Molly et al. (2014) Is American College of Surgeons NSQIP organ space infection a surrogate for pancreatic fistula? J Am Coll Surg 219:1111-6
Mathur, Abhishek; Al-Azzawi, Hayder H; Lu, Debao et al. (2008) Steatocholecystitis: the influence of obesity and dietary carbohydrates. J Surg Res 147:290-7
Graewin, Shannon J; Kiely, James M; Lu, Debao et al. (2008) Leptin regulates gallbladder genes related to gallstone pathogenesis in leptin-deficient mice. J Am Coll Surg 206:503-10
Al-Azzawi, Hayder H; Nakeeb, Attila; Saxena, Romil et al. (2007) Cholecystosteatosis: an explanation for increased cholecystectomy rates. J Gastrointest Surg 11:835-42;discussion 842-3
Mathur, Abhishek; Megan, Marine; Al-Azzawi, Hayder H et al. (2007) High dietary carbohydrates decrease gallbladder volume and enhance cholesterol crystal formation. Surgery 141:654-9
Mathur, Abhishek; Walker, Julia J; Al-Azzawi, Hayder H et al. (2007) Ezetimibe ameliorates cholecystosteatosis. Surgery 142:228-33
Graewin, Shannon J; Kiely, James M; Svatek, Carol L et al. (2006) Ciliary neurotrophic factor restores gallbladder contractility in leptin-resistant obese diabetic mice. J Surg Res 130:146-51
Nakeeb, Attila; Comuzzie, Anthony G; Al-Azzawi, Hayder et al. (2006) Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg 10:940-8; discussion 948-9
Al-Azzawi, Hayder H; Mathur, Abhishek; Lu, Debao et al. (2006) Pioglitazone increases gallbladder volume in insulin-resistant obese mice. J Surg Res 136:192-7
Goldblatt, Matthew I; Swartz-Basile, Deborah A; Al-Azzawi, Hayder H et al. (2006) Nonalcoholic Fatty gallbladder disease: the influence of diet in lean and obese mice. J Gastrointest Surg 10:193-201

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