GPR30 and hepatic cholesterol metabolism

摘要 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 研究了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。口服避孕药和结合雌激素显着增加胆结石患病率 绝经前和绝经后妇女。在患有前列腺疾病的男性中也发现了类似的结石效应 术后雌激素治疗期间的癌症。所有这些研究都表明，胆结石的易感性较高 女性与男性相比，与肝脏代谢胆固醇的方式不同有关。 雌激素。我们发表的研究表明，经典雌激素受体 α (ERα)，而不是 ERβ，在 肝脏在雌激素诱导的雌性小鼠胆结石中起着至关重要的作用。潜在的分子机制 随着雌激素在胆结石形成中的成石作用变得更加复杂 G 蛋白偶联受体 30 (GPR30)，一种新型雌激素受体。我们的基因分析发现 Gpr30 是小鼠体内的一种新胆结石基因 Lith18。我们发表的结果建立了一个新颖的概念 GPR30 参与雌激素依赖性成石作用，独立于 ERα 发挥作用，因为 GPR30 ERα可以通过不同途径促进雌激素诱发的胆结石的形成。然而， 确定 GPR30 的成岩机制一直是人们关注的焦点，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发的胆结石的易感性。我们假设 雌激素激活的 GPR30 通过表皮生长因子增强胆石生成 受体（EGFR）信号通路通过破坏肝脏胆汁酸代谢，促进胆汁 胆固醇分泌过多，损害胆囊排空和再充盈。这个假设是基于 我们新的初步数据表明 GPR30 主要定位于内质网 与主要存在于肝细胞核中的ERα完全不同。我们计划 为实现我们的目标，我们要实现以下三个具体目标：一是阐明机制 GPR30 的激活通过抑制肝脏胆汁酸合成来增强胆汁成石性 通过EGFR途径。其次，我们将研究 GPR30 关键作用背后的机制 促进胆汁胆固醇分泌过多。三、探讨GPR30是否损害胆囊 运动性导致固体胆固醇晶体快速生长和聚集而形成微石症。之后 完成拟议的研究后，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，并将发展新的概念来阐明重要的胆汁酸代谢 GPR30 在驱动过饱和胆汁和胆固醇结晶的启动中的作用，这两个关键步骤 胆结石形成的最早阶段。这些将帮助我们获得一些新颖的机制见解 女性雌激素诱发胆固醇胆结石的发病机制。

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.