法尼酯X受体通过ABCG2发挥降尿酸作用的机制研究

The decreased intestinal urate excretion caused by ATP-binding cassette transporter,subfamily G,member 2（ABCG2） dysfunction is a common mechanism in hyperuricemia. Farnesoid X receptor (FXR) is involved in the metabolic regulation of bile acids, lipids and carbohydrates, but its role in hyperuricemia has not been clarified. Our Previous experiments showed that the serum uric acid level increased in FXR knockout mice; FXR agonist GW4064 can prevent hyperuricemia and promote intestinal ABCG2 expression; FXR and ABCG2 expression were significantly decreased in the intestinal of hyperuricemia patients, and positively correlated with each other. Further study demonstrated that there might have potential FXR binding sites in ABCG2 promoter region. Here, we propose a hypothesis that FXR can induce ABCG2 expression in transcriptional level, and exerting anti-hyperuricemia effect by promoting intestinal uric acid excretion. We aim to use FXR knockout mice and hyperuricemia models to explore the anti-hyperuricemia effect of FXR and it’s possible mechanism ; Using in vitro study, we try to investigate the potential role of FXR in regulating ABCG2 expression; We attempt to evaluate correction between FXR and ABCG2 expression as well as the clinical significance in human intestinal tissues. This study can elucidate the anti-hyperuricemia effect of FXR, and also provide novel insight into the treatment of hyperuricenmia.

ATP结合盒转运蛋白G2（ABCG2）功能异常导致肠道尿酸排泄障碍是高尿酸血症的一个重要原因。法尼酯X受体（FXR）参与了胆汁酸、脂质以及糖类的代谢调控，而在高尿酸血症中的作用尚未明确。前期研究发现：FXR敲除小鼠血尿酸水平升高；FXR可降低高尿酸血症小鼠血尿酸水平，促进肠道ABCG2表达；高尿酸血症患者肠道组织FXR表达明显降低，与ABCG2表达呈正相关；进一步研究发现ABCG2启动子区可能存在FXR潜在的结合位点。在这里我们假设FXR通过增加肠道ABCG2表达促进肠道尿酸的排泌发挥降尿酸作用。本研究拟在体内动物水平探讨FXR降尿酸作用及可能机制；在体外细胞水平研究FXR调控ABCG2表达的分子机制；在临床水平评估FXR与ABCG2表达相关性。本研究不仅能够进一步阐明FXR降尿酸的机制，为其临床应用提供理论依据，更为未来降尿酸治疗提供新的思路。

ATP结合盒转运蛋白G2（ABCG2）功能异常导致肠道尿酸排泄障碍是高尿酸血症的一个重要原因。法尼酯X受体（FXR）参与了胆汁酸、脂质以及糖类的代谢调控，而在高尿酸血症中的作用尚未明确。本研究发现Fxr-/-小鼠血尿酸水平显著高于野生型小鼠；酵母膏饲喂联合尿酸酶抑制剂氧嗪酸钾腹腔注射可建立稳定的高尿酸血症模型，FXR可降低高尿酸血症小鼠血尿酸水平；高尿酸血症模型组小鼠肾脏以及肠道组织FXR以及ABCG2表达降低，而FXR激动剂奥贝胆酸干预处理后，激活的FXR明显促进了小鼠肠道组织以及肾脏组织尿酸转运体ABCG2的表达；体外研究也发现FXR正向调控ABCG2表达；进一步研究发现FXR通过与ABCG2启动子区域结合促进其表达。本研究明确了FXR降尿酸作用，发现FXR与ABCG2启动子区域结合促进其表达。这将有助于新型降尿酸药物的研发。.本课题组既往研究发现Sirt1参与了尿酸代谢，且具有抑制痛风发作的作用，但其具体机制不明。利用MSU晶体关节腔内注射建立痛风性关节炎小鼠模型，给予Sirt1激动剂白藜芦醇处理后痛风性关节炎小鼠关节肿胀明显减轻。Sirt1抑制了小鼠关节腔内炎症细胞浸润，同时降低了炎症因子IL-1β, IL-1α, IL-6,IFN-γ, MCP-1, TNF-α以及趋化因子CXCL-1, CXCL-5, CCL-22的表达；Sirt1促进了小鼠关节腔内PPARγ的表达；沉默PPARγ后，Sirt1抑制炎症作用明显降低。以上结果提示Sirt1可以抑制痛风性关节炎小鼠痛风发作，其机制可能是通过促进PPARγ表达发挥作用。为研究痛风药物提供新的靶点。