The deletion of the estrogen receptor α gene reduces susceptibility to estrogen-induced cholesterol cholelithiasis in female mice.
The deletion of the estrogen receptor α gene reduces susceptibility to estrogen-induced cholesterol cholelithiasis in female mice.
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DOI：
10.1016/j.bbadis.2015.07.020
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Wang DQ
中科院分区：
文献类型：
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作者：
de Bari O;Wang HH;Portincasa P;Liu M;Wang DQ
令人信服的证据表明，雌激素是胆结石形成的关键危险因素，并通过肝脏雌激素受体α（ERα）而不是ERβ促进胆固醇结石形成。为了研究雌激素通过ERα的致石机制，我们研究了Erα的缺失是否可以保护卵巢切除（OVX）雌性小鼠的胆石形成，这些小鼠喂食致石饮食并以0或6 μg/d的17β-雌二醇（E2）治疗56天。我们的研究结果表明，高剂量E2和致石饮食56天后，OVX ER α（+/+）小鼠的胆结石患病率从100%降至OVX ERα（−/−）小鼠的30%。与OVX ER α（+/+）小鼠相比，OVX ER α（−/−）小鼠的肝脏胆固醇分泌显著减少，即使喂食致石饲料并给予E2治疗56天。这些改变通过降低胆囊胆汁的胆固醇饱和指数来降低胆汁成石性。免疫组化结果显示ERα主要表达于胆囊平滑肌细胞。高水平的E2主要通过ERα和胆囊收缩素-1受体途径损害胆囊排空功能，导致OVX ERα（+/+）小鼠胆囊淤滞。相比之下，OVX ERα（−/−）小鼠的胆囊排空功能大大改善。这显著地延缓了胆固醇结晶以及固体胆固醇晶体生长和聚集成微结石和结石。总之，Erα的缺失通过减少雌性小鼠的肝脏胆固醇分泌、使胆囊胆汁去饱和和改善胆囊收缩功能来降低E2诱导的胆结石形成的易感性。
Compelling evidence has demonstrated that estrogen is a critical risk factor for gallstone formation and enhances cholesterol cholelithogenesis through the hepatic estrogen receptor α (ERα), but not ERβ. To study the lithogenic mechanisms of estrogen through ERα, we investigated whether the deletion of Erα protects against gallstone formation in ovariectomized (OVX) female mice fed a lithogenic diet and treated with 17β-estradiol (E2) at 0 or 6 μg/day for 56 days. Our results showed that the prevalence of gallstones was reduced from 100% in OVX ERα (+/+) mice to 30% in OVX ERα (−/−) mice in response to high doses of E2 and the lithogenic diet for 56 days. Hepatic cholesterol secretion was significantly diminished in OVX ERα (−/−) mice compared to OVX ERα (+/+) mice even fed the lithogenic diet and treated with E2 for 56 days. These alterations decreased bile lithogenicity by reducing cholesterol saturation index of gallbladder bile. Immunohistochemical studies revealed that ERα was expressed mainly in the gallbladder smooth muscle cells. High levels of E2 impaired gallbladder emptying function mostly through the ERα and cholecystokinin-1 receptor pathway, leading to gallbladder stasis in OVX ERα (+/+) mice. By contrast, gallbladder emptying function was greatly improved in OVX ERα (−/−) mice. This markedly retarded cholesterol crystallization and the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. In conclusion, the deletion of Erα reduces susceptibility to the formation of E2-induced gallstones by diminishing hepatic cholesterol secretion, desaturating gallbladder bile, and improving gallbladder contraction function in female mice.