GPR30 and Hepatic Cholesterol Homeostasis

GPR30 和肝脏胆固醇稳态

• 批准号: 9302754
• 负责人: DAVID Q WANG
• 金额: $ 33.47万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-25 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302754
• 关键词: 7alpha hydroxylase; Age; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; CYP7A1 gene; Cell Nucleus; Chemicals; Cholelithiasis; Cholesterol; Cholesterol Homeostasis; Clinical Research; Conjugated Estrogens; Crystallization; Data; Development; Diet; Dose; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Equilibrium; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogens; GPER gene; Gallbladder; Genes; Genetic; Goals; Hepatic; Hepatocyte; Human; Impairment; Knowledge; Liver; Liver Failure; Liver diseases; Malignant neoplasm of prostate; Mediating; Membrane; Metabolic; Metabolism; Mission; Molecular; Mucins; Mus; Oral Contraceptives; Output; Pathogenesis; Pathway interactions; Phenotype; Play; Population Study; Precipitation; Predisposition; Prevalence; Preventive Intervention; Publishing; Research; Risk; Risk Factors; Role; Solid; Solubility; Source; Therapeutic Intervention; Time; United States National Institutes of Health; Woman; Work; absorption; base; epidemiology study; estrogen receptor gamma; genetic analysis; innovation; insight; interest; men; novel; prevent; public health relevance; rapid growth; response

 DESCRIPTION (provided by applicant): Epidemiological and clinical studies have found that cholesterol gallstones are more prevalent in women than in men at all ages in every population studied. Accumulated evidence shows that the use of oral contraceptives and conjugated estrogens in women significantly increases the prevalence of gallstones. Estrogen therapy to men with prostatic cancer also leads to similar lithogenic effects. These findings clearly demonstrate that the increased risk of developing gallstones in women compared to men is related to differences in how the liver metabolizes cholesterol in response to estrogen. Our published studies have established a critical role for estrogen in enhancing cholelithogenesis by activating the classical estrogen receptor α (ERα), but not ERβ in the liver. However, the mechanisms mediating estrogen's lithogenic actions on gallstone formation have become more complicated with the identification of a novel estrogen receptor, the G protein-coupled receptor 30 (GPR30). Our genetic findings support the candidacy of GPR30 as a compelling gene underlying a new gallstone gene Lith18. However, identifying the lithogenic mechanisms of GPR30 has been a focal point of interest because it is still unknown whether GPR30 plays a major role in estrogen-induced gallstones and whether it acts independently of or in conjunction with ERα on inducing gallstone formation. We hypothesize that GPR30 is also involved in estrogen-dependent lithogenic actions, working independently of ERα, as both GPR30 and ERα can work through different pathways to promote the formation of estrogen-induced gallstones. This hypothesis is based on our new preliminary data showing that fed a lithogenic diet for 8 wk, ovariectomized GPR30(+/+)/ERα(-/-) mice still form gallstones in response to high doses of estrogen. By contrast, the prevalence of gallstones is significantly reduced in estrogen-treated GPR30(-/-)/ERα(-/-) mice compared to GPR30(+/+)/ERα(+/+) mice. Therefore, we plan to accomplish our goals by pursuing the following three specific aims: First, we will investigate the phenotypic characterization of GPR30 that determines susceptibility to cholesterol cholelithiasis. Second, we will study whether the activation of GPR30 leads to the lithogenesis of bile by inhibiting hepatic bile acid synthesis through the epidermal growth factor receptor (EGFR) pathway in response to high levels of estrogen. Third, we will elucidate the critical role of GPR30 in hepatic hypersecretion of biliary cholesterol and gallbladder hypomotility that accounts for rapid growth of cholesterol crystals. The proposed studies are innovative both conceptually and in the implementation of experimental approaches because distinguishing the lithogenic actions of GPR30 from those of ERα and further investigating how estrogen produces lithogenic actions through GPR30 will elucidate all the molecular mechanisms behind the formation of estrogen-induced gallstones. The planned experimental strategies are comprehensive, yet feasible. This project will help us gain novel mechanistic insight into the pathogenesis of estrogen-induced gallstones through GPR30 or ERα or both.

 描述（由申请人提供）：流行病学和临床研究发现，胆固醇结石在所有研究人群中的所有年龄段的女性中比男性更普遍。累积的证据表明，妇女使用口服避孕药和结合雌激素会显著增加胆结石的患病率。对前列腺癌患者进行雌激素治疗也会导致类似的致石作用。这些发现清楚地表明，与男性相比，女性患胆结石的风险增加与肝脏如何代谢胆固醇以应对雌激素的差异有关。我们已发表的研究表明，雌激素通过激活肝脏中的经典雌激素受体α（ERα）而不是ERβ，在促进胆石形成中发挥关键作用。然而，介导雌激素对胆结石形成的致石作用的机制随着新的雌激素受体G蛋白偶联受体30（GPR 30）的鉴定而变得更加复杂。我们的遗传学研究结果支持GPR 30作为一个令人信服的基因潜在的一个新的胆结石基因Lith 18的候选资格。然而，确定GPR 30的成石机制一直是人们关注的焦点，因为GPR 30是否在雌激素诱导的胆结石中起主要作用以及它是否独立或与ERα一起诱导胆结石形成仍然是未知的。我们假设GPR 30也参与雌激素依赖性的致石作用，独立于ERα发挥作用，因为GPR 30和ERα都可以通过不同的途径促进雌激素诱导的胆结石的形成。这一假设是基于我们新的初步数据，这些数据显示，喂食致石性饮食8周，卵巢切除的GPR 30（+/+）/ERα（-/-）小鼠仍然对高剂量雌激素产生反应而形成胆结石。相比之下，与GPR 30（+/+）/ER α（+/+）小鼠相比，雌激素处理的GPR 30（-/-）/ER α（-/-）小鼠的胆结石患病率显著降低。因此，我们计划通过追求以下三个具体目标来实现我们的目标：首先，我们将研究决定胆固醇胆石症易感性的GPR 30的表型特征。第二，我们将研究GPR 30的激活是否通过抑制肝胆汁酸的合成，通过表皮生长因子受体（EGFR）途径，在高水平的雌激素反应，导致胆汁的结石形成。第三，我们将阐明GPR 30在肝脏胆汁胆固醇分泌过多和胆囊运动不足中的关键作用，这是胆固醇晶体快速生长的原因。这些研究在概念上和实验方法上都是创新的，因为区分GPR 30和ERα的致石作用，并进一步研究雌激素如何通过GPR 30产生致石作用，将阐明雌激素诱导的胆结石形成背后的所有分子机制。计划的实验策略是全面的，但可行的。本研究将有助于我们从GPR 30或ERα或两者共同作用的角度对雌激素诱导的胆结石的发病机制进行新的认识。