OBESITY, LEPTIN AND GALLSTONE PATHOGENESIS

肥胖、瘦素和胆结石发病机制

• 批准号: 6634987
• 负责人: HENRY ANTHONY PITT
• 金额: $ 28.2万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634987
• 关键词: bile; cholecystectomy; cholelithiasis; cholesterol; clinical research; disease /disorder model; disease /disorder proneness /risk; gastrointestinal motility /pressure; genetic manipulation; hormone receptor; human subject; laboratory mouse; leptin; lipid metabolism; liver metabolism; obesity; pathologic process; protein structure function; receptor expression; serum; tissue /cell culture

DESCRIPTION (Verbatim from Applicant's Abstract): 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.

描述（逐字研究申请人的摘要）：大约有3万美国人有胆结石，绝大多数人超重。这 实验室的长期目标是了解 胆固醇胆石形成。胆结石的发病机理与 1）肝脂质代谢的改变，2）胆固醇晶体成核， 和/或3）胆道运动。胆结石最常见于肥胖， 中年妇女。最近的研究阐明了 胆结石发病机理中的性别，铁缺乏症和女性激素。 同样，瘦素的作用和其受体在 在过去的几年中，肥胖症的发病机理已被阐明。但是， 肥胖，瘦素和胆结石形成之间的联系仍然晦涩。 该实验室的最新数据是先天性肥胖的OB/OB小鼠，表明 它们在胆道脂质中发生变化，增强的胆固醇晶体形成 并增加了胆囊体积。瘦素受体也已被证明 在小鼠和人类的肝脏和胆汁树中。因此， 该提议的假设是其受体的瘦素或故障 通过 改变肝脂质代谢，胆固醇晶体成核和胆道 运动。两个相关的特定目标是1）确定肥胖是否是否 瘦素或瘦素受体故障改变a）肝脂质代谢，b） 胆固醇晶体成核和/或C）胆道运动，2）确定 瘦素的遗传改变及其受体是否在胆结石形成上 是加法的。在女性，瘦素缺乏ob/ob小鼠的初步研究 表明这些动物容易形成胆固醇。一个 OB/OB，OB +/-（杂合子），DB/DB（瘦素受体）的一系列研究 故障和Ay（Agouti黄色）小鼠以及遗传交叉的OB/OB和 提出了DB/DB小鼠，以剖析哪种致病机制联系在一起 瘦素和胆结石。同样，瘦和肥胖的胆汁血清和组织 进行胆囊切除术的人将被系统地研究以建立 临床相关性。这些研究应导致独特的策略 胆道预防，这是这项研究的最终目标。