甲状腺功能失调促进胆囊结石形成的机制研究（英文）

Thyroid dysfunction, either hyper or hypothyroidism, promotes gallstone formation by different mechanisms

目的:探究甲状腺功能失调(包括功能亢进或减退)对胆囊结石形成的影响,并初步探讨其作用机制。创新点:首次在胆囊结石小鼠模型中证实甲状腺功能失调(包括功能亢进或减退)将促进胆囊结石的形成,且此作用通过不同的分子调控机制。方法:应用性腺切除C57BL/6雄鼠构建胆囊结石动物模型,给予高脂饮食,分别观察饲养0、1、2、3、4、5、6、8、10周后胆囊结石形成情况。设置对照组(假手术+磷酸缓冲盐溶液(PBS)皮下注射)、甲状腺功能亢进组(假手术+三碘甲状腺原氨酸(T3)皮下注射)和甲状腺功能减退组(甲状腺次全切除+PBS皮下注射),给予高脂饮食5周,观察胆囊结石形成情况,收集肝脏组织用于测定核受体表达水平。用苏木精-伊红染色法(H&E)确定甲状腺切除,用酶联免疫吸附测定(ELISA)试剂盒检测血液甲状腺激素水平,用实时定量聚合酶链式反应(RT-PCR)测定肝脏核受体表达水平。结论:本实验通过观察高脂饮食不同时间阶段小鼠胆囊结石形成情况证实胆结石动物模型的构建成功(表1和图3)。ELISA实验结果显示,已成功构建甲状腺功能亢进和减退动物模型(图1)。甲状腺功能亢进通过上调核受体Lxrα、Rxr和Cyp7α1,下调Fxr表达而促进胆囊结石形成;甲状腺功能减退通过提高血清胆固醇水平以及下调Rxr表达促进胆囊结石形成(图4和5)。综上所述,甲状腺功能失调(包括甲状腺功能亢进和减退)通过不同的分子作用机制促进胆囊结石的形成。

We have investigated comprehensively the effects of thyroid function on gallstone formation in a mouse model. Gonadectomized gallstone-susceptible male C57BL/6 mice were randomly distributed into three groups each of which received an intervention to induce hyperthyroidism, hypothyroidism, or euthyroidism. After 5 weeks of feeding a lithogenic diet of 15% （w/w） butter fat, 1% （w/w） cholesterol, and 0.5% （w/w） cholic acid, mice were killed for further experiments. The incidence of cholesterol monohydrate crystal formation was 100% in mice with hyperthyroidism, 83% in hypothyroidism, and 33% in euthyroidism, the differences being statistically significant. Among the hepatic lithogenic genes, Tr~ was found to be up-regulated and Rxr down-regulated in the mice with hypothyroidism. In contrast, Lxra, Rxr, and Cyp7al were up-regulated and Fxr down-regulated in the mice with hyperthyroidism. In conclusion, thyroid dysfunction, either hyperthyroidism or hypothyroidism, promotes the formation of cholesterol gallstones in C57BL/6 mice. Gene expression differences suggest that thyroid hormone disturbance leads to gallstone formation in different ways. Hyperthyroidism induces cholesterol gallstone formation by regulating expression of the hepatic nuclear receptor genes such as Lxra and Rxr, which are significant in cholesterol metabolism pathways. However, hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis.