Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO.
Hepatology. 2020 Dec;72(6):2077-2089. doi: 10.1002/hep.31212. Epub 2020 Oct 22.
Estrogen is an important risk factor for cholesterol gallstone disease because women are twice as likely as men to form gallstones. The classical estrogen receptor α (ERα), but not ERβ, in the liver plays a critical role in the formation of estrogen-induced gallstones in female mice. The molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation have become more complicated with the identification of G protein-coupled receptor 30 (GPR30), an estrogen receptor.
We investigated the biliary and gallstone phenotypes in ovariectomized female GPR30 , ERα , and wild-type mice injected intramuscularly with the potent GPR30-selective agonist G-1 at 0 or 1 μg/day and fed a lithogenic diet for 8 weeks. The activation of GPR30 by G-1 enhanced cholelithogenesis by suppressing expression of cholesterol 7α-hydroxylase, the rate-limiting enzyme for the classical pathway of bile salt synthesis. These metabolic abnormalities led to an increase in biliary cholesterol concentrations in company with hepatic hyposecretion of biliary bile salts, thereby inducing cholesterol-supersaturated gallbladder bile and accelerating cholesterol crystallization. G-1 also impairs gallbladder emptying, leading to sluggish gallbladder motility and promoting the development of biliary sludge in the early stage of gallstone formation. The prevalence rates of gallstones were 80% in wild-type and ERα mice treated with G-1 compared to 10% in wild-type mice receiving no G-1. However, no gallstones were formed in GPR30 mice treated with G-1.
GPR30 produces additional lithogenic actions, working independently of ERα, to increase susceptible to gallstone formation in female mice; both GPR30 and ERα are potential therapeutic targets for cholesterol gallstone disease, particularly in women and patients exposed to high levels of estrogen.
雌激素是胆固醇性胆囊结石病的一个重要危险因素，因为女性形成胆囊结石的可能性是男性的两倍。肝脏中的经典雌激素受体 α（ERα），而不是 ERβ，在雌性小鼠中雌激素诱导的胆囊结石形成中起着关键作用。随着 G 蛋白偶联受体 30（GPR30），即雌激素受体的鉴定，雌激素对胆囊结石形成的致石作用的分子机制变得更加复杂。
我们研究了去卵巢雌性 GPR30、ERα 和野生型小鼠肌肉内注射强 GPR30 选择性激动剂 G-1（0 或 1μg/天）并给予致石饮食 8 周后的胆汁和胆囊结石表型。G-1 对 GPR30 的激活通过抑制胆固醇 7α-羟化酶（胆汁盐合成经典途径的限速酶）的表达来增强胆石形成。这些代谢异常导致胆汁胆固醇浓度升高，同时伴有肝胆汁盐分泌减少，从而诱导胆固醇过饱和的胆囊胆汁，并加速胆固醇结晶。G-1 还损害胆囊排空，导致胆囊运动缓慢，并在胆石形成的早期促进胆泥的形成。用 G-1 处理的野生型和 ERα 小鼠的胆囊结石发生率为 80%，而未用 G-1 处理的野生型小鼠为 10%。然而，用 G-1 处理的 GPR30 小鼠没有形成胆囊结石。
GPR30 产生了额外的致石作用，独立于 ERα 作用，增加了雌性小鼠对胆囊结石形成的易感性；GPR30 和 ERα 都是胆固醇性胆囊结石病的潜在治疗靶点，特别是在女性和暴露于高水平雌激素的患者中。
