PCSK9基因多态性与外泌体介导的代谢综合征脂质代谢机制的研究

Metabolic syndrome (MS) is a complex genetic disease. Cardiovascular diseases is the main clinical consequences of MS. Lipid metabolism disorders is the main element of cardiovascular events. PCSK9 and LDLR play an important role in the lipid metabolism of hepatocytes. PCSK9 has regulatory effect on LDLR, and the PCSK9 gene E670G polymorphism may affect the function of LDLR, and then affect the metabolism of LDL-C and other lipid components, the exosomes from Hepatocyte may play an important role in this process. In order to prove that the PCSK9 gene polymorphism may affect the function of PCSK9 and LDLR protein in the exosomes of hepatocytes and hepatocytes, and then affect lipid metabolism, which lead to the development of MS and related diseases. This study intends to explore the relationship between the PCSK9 gene polymorphism and the lipid metabolism mediated by exosomes at the crowd, cells and overall levels. In addition, the mechanism of PCSK9 and LDLR in the exosomes of hepatocytes will be studied, which will provide theory basis to elucidate the cause of the occurrence and development of cerebrovascular disease induced by MS, provide the basis for exploring effective new therapeutic targets and provide theoretical basis and experimental foundation for the realization of comprehensive prevention and control.

代谢综合征是一种复杂的遗传性疾病，心脑血管疾病是代谢综合征的主要临床后果，脂质代谢紊乱是心脑血管事件发生的重要因素。PCSK9和LDLR在肝细胞的脂质代谢中发挥了重要作用，PCSK9对LDLR有调节作用，PCSK9基因E670G多态性可能影响LDLR的功能，进而影响了LDL-C及其他脂质成分的代谢，而肝细胞来源的外泌体可能在其中扮演重要角色。为了证明代谢综合征状态下，PCSK9基因多态性可能通过影响肝细胞及肝细胞来源的外泌体中PCSK9和LDLR蛋白的功能，影响脂质代谢，进而导致代谢综合征相关疾病的发生发展。本课题拟从人群、细胞和整体水平探讨代谢综合征PCSK9基因多态性与外泌体介导的脂质代谢的关系，并以外泌体为单位，研究PCSK9和LDLR在肝细胞来源的外泌体中的作用机制，为我们阐明代谢综合征心脑血管疾病的发生发展提供新的依据，探索可能的治疗靶点，为实现综合防治提供理论依据和实验基础。

背景:LDLR是循环中清除胆固醇的主要途径，PCSK9是一种分泌的蛋白酶，与LDLR蛋白结合并促进其降解。本病例对照研究的目的是探讨可溶性LDLR (sLDLR)和PCSK9在冠状动脉疾病(CAD)中的作用，并研究这两个指标与CAD的关系。方法:在2018年1月至2018年8月招募的144例中国患者中，根据人口学和病史，采用倾向评分匹配法(PSM)选择冠状动脉造影(CAG)特征的轻、重度狭窄患者81例，健康对照组63例。采用酶联免疫吸附法(ELISA)、免疫沉淀法(IP)和免疫印迹法(western blotting)检测sLDLR和PCSK9的浓度。多因素logistic模型被用来评估冠状动脉狭窄程度和生物学指标之间的相关性。结果:PCSK9水平的升高是冠状动脉狭窄发生的重要预测因子，与重度冠状动脉狭窄患者相比(OR=1.016, 95%CI: 1.009, 1.024)和轻度冠状动脉狭窄患者相比(OR=1.009, 95%CI: 1.003, 1.015)。sLDLR是混淆因子。与轻度狭窄患者相比，重度狭窄患者的PCSK9水平也较高(OR=1.007, 95%CI: 1.001, 1.013)。结论:这些发现提示PSCK9水平升高可能与冠脉狭窄程度升高有关，为PCSK9作为生物学指标应用于临床提供了依据。