GPR30 and hepatic cholesterol metabolism

GPR30 与肝脏胆固醇代谢

• 批准号: 10430167
• 负责人: JEFFREY E. PESSIN
• 金额: $ 46.89万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430167
• 关键词: 7alpha hydroxylase; Age; Agonist; Automobile Driving; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; Biliary Sludge; CYP7A1 gene; Cell Nucleus; Cholelithiasis; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Research; Conjugated Estrogens; Coupled; Crystallization; Data; Development; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Epithelial Cells; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogens; Exposure to; Female; GPER gene; Gallbladder; Gallbladder Emptying; Genes; Goals; Hepatic; Hepatocyte; Human; Impairment; Liver; Liver Failure; Liver diseases; Malignant neoplasm of prostate; Membrane; Metabolic; Mission; Molecular; Mucins; Mus; Oral Contraceptives; Output; Pathogenesis; Pathway interactions; Patients; Play; Population Study; Postmenopause; Postoperative Period; Predisposition; Pregnancy; Premenopause; Prevalence; Publishing; Research; Risk; Risk Factors; Role; Signal Pathway; Smooth Muscle; Solid; Solubility; Source; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; Wild Type Mouse; Woman; absorption; base; bile acid metabolism; cell motility; epidemiology study; gallstone disease; genetic analysis; innovation; insight; interest; men; novel; prevent; preventive intervention; rapid growth; response

Abstract Clinical and epidemiological studies have clearly demonstrated that women are twice as likely as men to form cholesterol gallstones at all ages studied, indicating that estrogen is an important risk factor for cholesterol gallstone disease. Oral contraceptives and conjugated estrogens significantly increase gallstone prevalence in premenopausal and postmenopausal women. Similar lithogenic effects are also found in men with prostate cancer during postoperative estrogen therapy. All these studies indicate that high susceptibility to gallstones in women compared with men is related to differences in how the liver metabolizes cholesterol in response to estrogen. Our published studies have shown that the classical estrogen receptor α (ERα), but not ERβ, in the liver plays a critical role in estrogen-induced gallstones in female mice. The molecular mechanisms underlying the lithogenic role of estrogen in gallstone formation have become more complicated with the identification of the G protein-coupled receptor 30 (GPR30), a novel estrogen receptor. Our genetic analysis has found that Gpr30 is a new gallstone gene, Lith18, in mice. Our published results have established a novel concept that GPR30 is involved in estrogen-dependent lithogenic actions, working independently of ERα, as both GPR30 and ERα can promote the formation of estrogen-induced gallstones through different pathways. However, identifying the lithogenic mechanisms of GPR30 has been a focal point of interest because it remains elusive how GPR30 increases susceptibility to estrogen-induced gallstones at a molecular level. We hypothesize that GPR30 activated by estrogen enhances cholelithogenesis through the epidermal growth factor receptor (EGFR) signaling pathway by disrupting hepatic bile acid metabolism, promoting biliary cholesterol hypersecretion, and impairing gallbladder emptying and refilling. This hypothesis is based on our new preliminary data showing that GPR30 is localized predominantly in the endoplasmic reticulum of hepatocytes, which is completely different from ERα that resides mainly in the nucleus of hepatocytes. We plan to accomplish our goals by pursuing the following three specific aims: First, we will elucidate the mechanisms whereby the activation of GPR30 enhances the bile lithogenicity by inhibiting hepatic bile acid synthesis through the EGFR pathway. Second, we will investigate the mechanisms underlying the critical role of GPR30 in promoting biliary cholesterol hypersecretion. Third, we will explore whether GPR30 impairs gallbladder motility that accounts for rapid growth and agglomeration of solid cholesterol crystals to microlithiasis. After completing the proposed studies, our results will present a new view on how GPR30 regulates cholesterol and bile acid metabolism in the liver, bile, and gallbladder, and will develop novel concepts to elucidate the vital roles of GPR30 in driving the initiation of supersaturated bile and cholesterol crystallization, two key steps in the earliest stage of gallstone formation. These would help us gain some novel mechanistic insights into the pathogenesis of estrogen-induced cholesterol gallstones in women.

抽象的 临床和流行病学研究清楚地表明，女性形成的可能性是男性的两倍 在所有年龄段的胆固醇胆结石，表明雌激素是胆固醇的重要危险因素 胆结石疾病。口服避孕药和共轭进化可显着增加胆结石的患病率 绝经后和绝经后妇女。前列腺男性也发现了类似的岩性作用 术后雌激素治疗期间的癌症。所有这些研究表明，对胆结石的敏感性很高 与男性相比，女性与肝脏如何代谢胆固醇的差异有关 我们已发表的研究表明，经典的雌激素受体α（ERα），但不是ERβ 肝脏在雌激素诱导的雌性小鼠胆结石中起关键作用。分子机制 雌激素在胆结石形成中的岩性作用已随着鉴定而变得更加复杂 G蛋白偶联受体30（GPR30），一种新型的雌激素受体。我们的遗传分析发现 GPR30是一个新的胆结石基因，lith18，在小鼠中。我们发表的结果已经建立了一个新颖的概念 GPR30参与雌激素依赖性的岩性作用，独立于ERα，作为GPR30 ERα可以通过不同的途径促进雌激素诱导的胆结石的形成。然而， 识别GPR30的岩性机制一直是关注点，因为它仍然难以捉摸 GPR30如何在分子水平上增加对雌激素诱导的胆结石的敏感性。我们假设这一点 雌激素激活的GPR30通过表皮生长因子增强了杂化岩发生 受体（EGFR）信号通路通过破坏肝胆汁代谢，促进胆道 胆固醇过度分泌，并损害胆囊排空和补充。该假设基于 我们的新初步数据表明，GPR30主要在内质网中定位 肝细胞与主要存在于肝细胞核的ERα完全不同。我们计划 通过追求以下三个特定目标来实现我们的目标：首先，我们将阐明机制 因此，GPR30的激活通过抑制肝胆酸合成来增强胆汁岩性 通过EGFR路径。其次，我们将研究GPR30关键作用的基础机制 在促进胆固醇过度分泌时。第三，我们将探索GPR30是否会损害胆囊 固体胆固醇晶体对微石症的快速生长和凝聚的动力。后 完成拟议的研究，我们的结果将对GPR30如何调节胆固醇和 肝脏，胆汁和胆囊中的胆汁酸代谢，并将发展新颖的概念以阐明重要 GPR30在推动超饱和胆汁和胆固醇结晶的倡议中的作用，这是两个关键步骤 胆结石形成的最早阶段。这些将有助于我们获得一些新颖的机械见解 雌激素诱导的女性胆固醇胆结石的发病机理。