高尿酸血症通过上调PTP1B诱发血清胆固醇升高的作用及分子机制研究

Hyperuricemia becomes one of the major global issues that harm human health, due to its morbidity increases year by year. Epidemiologic studies showed that hyperuricemia could predict the risk of a variety of metabolic diseases independently, but its pathogenic mechanism has not been elucidated. Our preliminary studies have found that hyperuricemia would induce abnormal up-regulation of cholesterol in pathologic rats’ serum. Further, it was demonstrated that the expression level of phosphorylase PTP1B in upstream of leptin signaling pathway was up-regulated, while the phosphorylation STAT3 was inhibited. Based on the above results, we proposed that increased uric acid is able to up-regulate serum cholesterol, which was attributed to the fact that uric acid inhibited Leptin-STAT3 signaling pathway via increasing the expression level of PTP1B. Therefore, based on our previous studies, we will assess the effects of PTP1B and Leptin-STAT3 signaling pathway on the level of cholesterol in hyperuricemia using the experimental animal models, and analyse the detailed metabolic mechanism that disturbs the cholesterol metabolism in livers by the metabonomics. Moreover, we will investigate how the high level of uric acid affects the cholesterol metabolism via the regulation of PTP1B in liver cells, and then elucidate its underlying molecular mechanism in this project. The successful implementation of this project will further reveal the pathogenic role of hyperuricemia, and assist to map the abnormal metabolism networks of liver. However, as far as we know, few research about hyperuricemia could up-regulate the expression of PTP1B, inhibit the leptin signaling pathway and molecular mechanisms of up-regulated the level of serum cholesterol have been reported. Therefore, this proposal is of great theoretical importance with obvious translational potentials.

高尿酸血症的发病率逐年攀升，已成为危害人们健康的全球性问题之一。高尿酸血症能独立预测多种疾病的发生，但致病机制尚未阐明。我们前期研究发现高尿酸血症大鼠血清胆固醇升高，预实验结果显示该大鼠肝脏瘦素通路中p-STAT3被抑制，其上游调控因子PTP1B发生明显上调。因此，我们推测尿酸可上调肝脏PTP1B而抑制Leptin-STAT3信号通路从而影响胆固醇代谢。本项目拟在动物水平研究肝脏PTP1B及Leptin-STAT3通路在高尿酸血症诱导胆固醇升高中的作用，并应用代谢组学分析其干扰胆固醇代谢的具体代谢调控机制；在细胞水平深入探讨高浓度尿酸通过PTP1B调控胆固醇代谢的分子机制。本项目顺利实施可帮助绘制高尿酸血症疾病状态下肝脏代谢网络，确证其对脂代谢紊乱等疾病的促进作用。目前尚无高尿酸血症上调PTP1B、抑制瘦素信号通路，及通过后二者介导血清胆固醇升高的相关报道，该研究具有一定创新性。

高尿酸血症的发病率逐年攀升，已成为危害人们健康的全球性问题之一。高尿酸血症能独立预测多种疾病的发生，但致病机制尚未阐明。本研究首先收集了健康人和高尿酸血症患者各100份血样进行了血生化分析，发现高尿酸血症患者中血脂异常者比例更高。随后，建立高尿酸血症小鼠模型，通过血生化、肝脏脂质检测以确证高尿酸可诱发脂代谢紊乱。收集对照组、模型组和降尿酸治疗组小鼠肝脏：一方面，检测小鼠肝脏中PTP1B及Leptin-STAT3通路变化，证实高尿酸可上调PTP1B而降低p-STAT3；另一方面，对肝组织进行脂质组学分析，比较对照组和高尿酸血症组的脂质，发现差异脂质主要集中于甘油磷脂通路，该通路中代谢酶LPCAT3在模型组中显著上调。接着，我们在人正常肝细胞L02和肝癌细胞HepG2中，探讨了高浓度尿酸对PTP1B及Leptin-STAT3信号通路的影响、对LPCAT3及甘油磷脂代谢通路的作用，发现高浓度尿酸可上调PTP1B而增加STAT3的去磷酸化导致p-STAT3降低，亦可上调LPCAT3而导致磷脂酰胆碱的组成发生改变、SREBP-1c发生激活。而细胞水平上干扰LPCAT3的表达可显著减弱高尿酸诱发的p-STAT3的抑制、SREBP-1c的激活和脂质代谢紊乱。综上，高尿酸可上调肝脏PTP1B而抑制Leptin-STAT3信号通路从而影响脂质代谢，并通过上调LPCAT3激活SREBP-1c诱导脂质代谢紊乱。PTP1B和LPCAT3可能是高尿酸血症诱发脂代谢紊乱的关键调节因子。这些结果进一步确证了高尿酸血症对脂代谢紊乱的促进作用，这可能为高尿酸血症的临床治疗提供新的见解，为高尿酸血症相关的代谢性疾病如代谢综合征等的治疗提供潜在靶点。