APOC3, HDL Function and Cardiovascular Complications of T1DM

 简介：心血管疾病(CVD)是1型糖尿病(T1 DM)的并发症，占死亡人数最多的疾病。T1 DM加重心血管疾病风险和潜在动脉粥样硬化的机制尚不清楚。初步研究表明，心血管疾病风险增加的T1 DM患者的高密度脂蛋白相关载脂蛋白C3(APOC3)水平升高，这些变化在T1 DM加速动脉粥样硬化的小鼠模型中复制。重要的是，已知APOC3基因的功能丧失突变可以降低人类的甘油三酯和心血管疾病的风险。甘油三酯和高密度脂蛋白代谢有着千丝万缕的联系。然而，关于APOC3对高密度脂蛋白结构和心脏保护功能的影响，人们知之甚少。此外，最近的临床研究表明，高密度脂蛋白调节巨噬细胞类固醇外流的能力受损是健康人类未来心血管事件的最强预测因素。拟议的研究结合了对人类T1 DM心血管疾病风险的前瞻性研究和对T1 DM小鼠模型的高度机械性研究，从而达到了RFA-DK-14-017的目标。假设高密度脂蛋白-APOC3与T1 DM患者未来发生心血管事件的风险相关，其潜在机制涉及由APOC3介导的高密度脂蛋白功能障碍(例如，类固醇外排能力降低)。具体目的是解决两个关键问题：目的1.高密度脂蛋白中的载脂蛋白C3水平是否可以预测T1 DM患者未来心血管事件的风险？将对匹兹堡糖尿病并发症流行病学(EDC)研究和1型糖尿病冠状动脉钙化(Cacti)研究这两项前瞻性研究中的大量T1 DM受试者的高密度脂蛋白指标进行病例对照研究。为了确定高密度脂蛋白的蛋白质含量或高密度脂蛋白颗粒数量的变化是否会导致高密度脂蛋白功能障碍和心血管疾病风险增加，这些研究将比较从T1 DM心血管疾病患者和对照中分离出来的高密度脂蛋白促进类固醇外流的能力。APOC3的丰富与高密度脂蛋白的类固醇外流能力的丧失相关，这将有力地支持APOC3导致高密度脂蛋白功能障碍的说法，以及这种异常的高密度脂蛋白增加了T1 DM的心血管风险。目的2.载脂蛋白C3是否促进T1 DM小鼠模型的高密度脂蛋白功能障碍和动脉粥样硬化？初步数据表明，T1 DM加速动脉粥样硬化的小鼠模型模拟了有心血管疾病风险的T1 DM人高密度脂蛋白水平，而且APOC3直接或间接损害了高密度脂蛋白的功能。这项拟议的研究将评估APOC3缺乏或功能丧失的APOC3突变体是否可以减少T1 DM加速的动脉粥样硬化，并将利用APOC3-/-小鼠和APOC3的肝脏表达来探讨其潜在机制。此外，还将阐明高血糖和胰岛素缺乏对肝脏APOC3表达的调节，以及糖尿病和APOC3对高密度脂蛋白指标的影响。

 DESCRIPTION: Cardiovascular disease (CVD) is the complication of type 1 diabetes mellitus (T1DM) that accounts for the most mortality. The mechanism whereby T1DM exacerbates CVD risk and the underlying atherosclerosis is poorly understood. Preliminary studies suggest that T1DM subjects who are at increased risk of CVD have elevated levels of HDL-associated apolipoprotein C3 (APOC3), and that these changes are replicated in a mouse model of T1DM-accelerated atherosclerosis. Importantly, loss-of-function mutations in the APOC3 gene are known to reduce triglycerides and CVD risk in humans. Triglyceride and HDL metabolism are inextricably linked. However, little is known about the impact of APOC3 on HDL's structure and cardioprotective function. Moreover, recent clinical studies demonstrate that an impaired ability of HDL to mediate sterol efflux from macrophages is the strongest predictor of future CVD events in healthy humans. The proposed studies address the goals of RFA-DK-14-017 by combining prospective studies of CVD risk in T1DM humans and highly mechanistic studies in a mouse model of T1DM. It is hypothesized that HDL-APOC3 associates with the risk of future CVD events in T1DM patients and that the underlying mechanism involves HDL dysfunction (e.g. reduced sterol efflux capacity) mediated by APOC3. The specific aims are to address two key questions: Aim 1. Does the level of APOC3 in HDL predict the risk of future CVD events in patients with T1DM? Case-control studies on HDL metrics of large numbers of T1DM subjects from two prospective studies: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study and the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study will be performed. To determine whether alterations in HDL's protein cargo or HDL particle number generate dysfunctional HDL and increased CVD risk, these studies will compare the abilities of HDL isolated from T1DM CVD cases and controls to promote sterol efflux. Demonstrating that enrichment in APOC3 associates with loss of HDL's sterol efflux capacity would strongly support the proposal that APOC3 contributes to dysfunctional HDL and that such abnormal HDL increases CVD risk in T1DM. Aim 2. Does APOC3 promote HDL dysfunction and atherosclerosis in a mouse model of T1DM? Preliminary data suggest that a mouse model of T1DM-accelerated atherosclerosis mimics the higher APOC3 levels seen in HDL of T1DM humans at risk for CVD, and that APOC3 directly or indirectly impairs HDL function. The proposed studies will evaluate whether APOC3 deficiency or a loss-of-function APOC3 mutant reduces T1DM-accelerated atherosclerosis, and will investigate the underlying mechanisms using Apoc3-/- mice and hepatic expression of APOC3. The regulation of hepatic APOC3 expression by hyperglycemia and insulin deficiency and the effect of diabetes and APOC3 on HDL metrics will also be clarified.