雌二醇通过ER/ERE途径调控ABCG2促进肠道尿酸排泄的机制研究

There is a significant gender difference in the incidence of gout and hyperuricemia, and the mechanisms are not yet clear. ABCG2 is a recently discovered transporter that criticallty regulates intestinal uric acid excretion. We have recently found that estradiol could obviously decrease the level of serum uric acid in hyperuricemic mice, with a clear increase of ABCG2 in the intestine but not in the renalepithelium. Thus we propose that estradiol promotes uric acid excretion in the body mainly through regulation of intestinal ABCG2. This study aims to clarify the function and underlying mechanisms of estradiol in promotion of uric acid excretion by regulating intestinal ABCG2. We will use mouse intestinal fistulization-intestinal fluid recovery model to detect intestinal uric acid excretion of estradiol treated Abcg2 knock out and wild type mice with hyperuricemia. In vitro, we will use related siRNA to interfere certain molecules in intestinal epithelial cells, and to detect the rate of uric acid transportation and to investigate the role of ER/ERE pathway. The purpose of this study is to provide a theoretical basis for the gender differences in the incidence of gout and hyperuricemia, and to find a new therapeutic target for uric acid lowering therapy.

痛风/高尿酸血症的发病存在明显的性别差异，其机制目前尚未明确。ABCG2是新近发现的调控肠道尿酸排泄的重要转运体。我们前期研究发现，雌二醇可显著降低高尿酸血症小鼠血尿酸水平，上调肠道ABCG2，但未明显改变肾脏ABCG2表达，据此我们推测雌二醇在体内主要通过调控肠道ABCG2促进尿酸排泄。本项目拟建立肠道尿酸排泄体内体外模型，进一步阐明雌二醇调控肠道ABCG2促尿酸排泄的作用及其机制。体内研究拟利用小鼠肠道造瘘-肠液回收模型，检测经雌二醇干预的Abcg2敲除及野生型高尿酸血症小鼠肠道尿酸排泄量，阐明雌二醇的降尿酸作用是否通过肠道ABCG2。体外研究拟利用相关siRNA干预肠道上皮细胞，观察尿酸转运率，并研究ER/ERE在雌二醇调控肠道细胞ABCG2中的作用。本课题旨在为痛风/高尿酸血症发病的性别差异现象提供理论依据，并为降尿酸治疗提供新的治疗靶点。

目的。研究高尿酸血症的性别差异不仅可以为这一临床现象提供理论依据，还可以为降尿酸治疗提供新的治疗靶标。在本研究中，我们旨在证实雌二醇可以促进肠道三磷酸腺苷结合转运蛋白G超家族成员2（ATP-binding cassette superfamily G member 2, ABCG2）的表达，通过PI3K/Akt途径增加尿酸盐的排泄。.方法。比较高尿酸血症/痛风患者和健康对照组的雌二醇水平，并采用高尿酸血症小鼠模型（雄鼠雌二醇干预模型，雌鼠去势模型）观察雌二醇的降尿酸作用及ABCG2在肾脏和肠道的表达变化。建立小鼠肠道尿酸排泄和Caco-2细胞构建的体外尿酸转运模型，验证雌二醇调节的尿酸盐转运功能。探讨了雌二醇调节肠道细胞中ABCG2表达的分子途径。.结果。高尿酸血症/痛风患者的雌二醇水平明显低于健康对照组的水平。对雄性高尿酸血症小鼠和切除卵巢后的雌性高尿酸血症小鼠给予苯甲酸雌二醇（EB），证实雌二醇的降尿酸作用。高尿酸血症和雌二醇可上调肠道ABCG2的表达，对肾脏雌二醇ABCG2无明显上调作用。雌二醇在体内和体外肠道尿酸盐排泄模型中通过上调ABCG2的表达促进尿酸转运。雌二醇通过PI3K/Akt途径调控肠道ABCG2的表达。.结论。我们的研究发现雌二醇可通过PI3K/Akt途径调节肠道ABCG2，促进尿酸盐排泄，从而降低血清尿酸盐水平。既为高尿酸血症的性别差异现象提供了理论支持，也为降尿酸治疗提供了新的思路。