雌二醇调控肠道SLC2A9在高尿酸血症中的作用及机制研究

已有研究提示雌激素对高尿酸血症的发生发展具有重要作用，但具体机制未明。除肾脏外，肠道尿酸排泌异常也是高尿酸血症产生的重要原因，已知SLC2A9是具有高容量尿酸转运功能的通道蛋白，其肠上皮细胞特异性基因敲除小鼠可自发高尿酸血症。我们前期研究发现，雌二醇替代治疗可降低去势高尿酸血症小鼠血尿酸，增加肠道尿酸排泄，而肾脏尿酸排泄无变化，同时在上述过程中小鼠空肠SLC2A9表达上调。体外细胞实验发现SLC2A9受p53调控。据此我们提出假说，雌二醇可通过调控p53信号通路，促进肠道SLC2A9的表达和功能，进而调节肠道尿酸排泌实现降低血尿酸的作用。本研究拟以去势高尿酸血症小鼠模型和连续培养的小肠细胞系为实验平台，在体内和体外探索雌二醇对肠道SLC2A9表达的调控机制及其对尿酸排泌的影响，通过构建肠上皮细胞特异性Slc2a9基因敲除小鼠，进一步验证上述机制，为高尿酸血症的治疗和预防提供新思路。

A great deal of researches have revealed that estrogen played an important role in hyperuricemia. However, the detail mechanism remains unclear. Besides the kidney, the intestine is one of the most important organs involved in uric acid excretion. Known SLC2A9, a channel protein, is mainly a high-capacity urate transporter, and the enterocyte-specific SLC2A9 knockout mice can be spontaneous hyperuricemia. In our previous study, we found that 17α-estradiol replacement in the animal model with hyperuricemia established in the gonadectomized mice decreased the SUA level, increased the urate excretion from the intestine but had no effect on the fractional excretion of urate in the kidney. Moreover, estradiol replacement also increased the expression of SLC2A9 in the ileum. Meanwhile, in vitro experiments revealed that SLC2A9 expression was modulated by p53 signaling. Accordingly, our hypothesis is that 17α-estradiol could reduce the SUA level and facilitate gut excretion of UA through the regulation of p53 to promote the expression of SLC2A9 in intestine. To investigate the effect and mechanism of estradiol on hyperuricemia, both in vitro and in vivo studies were performed. Enterocyte-specific Slc2a9-deficient mice were generated to verify the effect and the mechanism. This study may provide a promising strategy for hyperuricemia.