ApoCIII掺入对HDL胆固醇流出功能影响及其机制探讨

HDL胆固醇流出功能比HDL-C水平更能预测冠心病风险。HDL的胆固醇流出易受体内环境的影响，但其机制不明。前期研究发现冠心病患者HDL中ApoCIII水平与胆固醇流出功能负相关，体外掺入ApoCIII降低HDL的胆固醇流出。已知B族I型清道夫受体（SR-BI）为介导HDL胆固醇流出的主要受体，也可结合ApoCIII，推测：HDL中的ApoCIII可通过SR-BI途径抑制HDL胆固醇流出。ApoCIII结合SR-BI可能干扰HDL与SR-BI的结合及其内吞-再分泌，抑制胆固醇流出。本项目拟先观察HDL中ApoCIII对HDL胆固醇流出的影响，接着明确ApoCIII掺入HDL影响胆固醇流出的关键途径，再了解其对HDL与SR-BI结合、内吞再分泌的影响，并通过ApoCIII点突变探讨其与SR-BI结合的关键结构，从而阐明ApoCIII掺入HDL影响胆固醇流出的机制，为改善HDL功能提供新思路。

Cholesterol efflux capacity of high density lipoprotein (HDL) has been proved to be a more reliable biomarker for atherosclerotic risk than HDL-cholesterol (HDL-C). However, HDL cholesterol efflux capacity is susceptible to internal environment and thus variable. Our previous work has demonstrated that the content of apolipoprotein C-III(apoCIII) in HDL correlates inversely with HDL cholesterol efflux capacity and incorporation of apoCIII with HDL in vitro can impair HDL cholesterol efflux capacity. Scavenger-receptor BI (SR-BI) is the main receptor to mediate HDL cholesterol efflux and apoCIII can bind with it. Based on these findings, we deduced that the combination of apoCIII with SR-BI may block HDL binding to SR-BI and interrupt HDL endocytosis as well as resecretion, leading to the impairment of HDL cholesterol efflux capacity. Our project will investigate the effects of apoCIII in HDL on cholesterol efflux capacity and elucidate the detailed mechanism including the pathway apoCIII takes to abrupt the cholesterol efflux, the effect of apoCIII on HDL recycling on cell models and the crucial structure of apoCIII to bind with SR-BI via apoCIII gene mutation. This study is expected help us understand how apoCIII affect the cholesterol efflux capacity of HDL and provide a potential new strategy to improve HDL function.