GPR30 and hepatic cholesterol metabolism

摘要 临床和流行病学研究清楚地表明，女性形成癌症的可能性是男性的两倍。 研究表明，雌激素是胆固醇的重要危险因素。 胆石症。口服避孕药和结合雌激素显著增加胆结石患病率 绝经前和绝经后妇女。在患有前列腺癌的男性身上也发现了类似的致结石作用。 癌症患者术后接受雌激素治疗。所有这些研究都表明，老年人对胆结石的易感性 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。我们已发表的研究表明，经典的雌激素受体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关键作用。潜在的分子机制 雌激素在胆结石形成中的致石作用已变得更加复杂。 G蛋白偶联受体30(GPR30)，一种新的雌激素受体。我们的基因分析发现 Gpr30是一种新的胆结石基因，名为Lith18，在小鼠体内。我们发表的结果建立了一个新的概念， Gpr30参与雌激素依赖的致石作用，独立于ERα发挥作用，因为两者 ERα可通过不同途径促进雌激素诱导的胆结石形成。然而， 确定GPR30的致石机制一直是人们感兴趣的焦点，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导的胆结石的易感性。我们假设 雌激素激活的GPR30通过表皮生长因子促进胆结石形成 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，影响胆囊排空和再充盈。这一假设是基于 我们新的初步数据显示，GPR30主要定位于人的内质网。 肝细胞，这与ERα完全不同，ER DNA主要位于肝细胞核。我们计划 为了实现我们的目标，我们追求以下三个具体目标：第一，我们将阐明机制 GPR30的激活通过抑制肝脏胆汁酸的合成增强胆汁的致石性 通过EGFR途径。第二，我们将研究GPR30关键作用的潜在机制 促进胆汁胆固醇高分泌。第三，我们将探讨GPR30是否会损害胆汁 导致固体胆固醇晶体快速生长和聚集成微结石的动力。之后 完成拟议的研究，我们的结果将为GPR30如何调节胆固醇和 胆汁酸在肝脏、胆汁和胆囊中的代谢，并将发展新的概念来阐明至关重要的 GPR30在启动胆汁过饱和和胆固醇结晶中的作用 胆结石形成的最早阶段。这些将帮助我们获得一些新的机械洞察 雌激素诱导的女性胆固醇结石的发病机制。

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.