Apolipoprotein C3-loading of apolipoprotein B100 lipoproteins and cardiovascular disease in patients with type 1 diabetes

我们最近发现，血清载脂蛋白C3(APOC3)水平可以预测心血管疾病的发生 (CVD)仙人掌，一项对1型糖尿病(T1 DM)受试者的前瞻性研究。在互补中 机制研究，我们发现用反义寡核苷酸(ASO)降低APOC3水平可以预防 小鼠T1 DM模型病变进展与载脂蛋白B(APOB)脂蛋白 加速糖尿病动脉粥样硬化。这些观察结果很重要，因为它们有力地支持了 APOC3在人类和小鼠的T1 DM环境中促进动脉粥样硬化的提议。这是 特别重要的是因为ASO对APOC3的研究正在人类中进行，这增加了它的可能性 可能通过降低载脂蛋白C3水平来降低T1 DM患者的心血管风险。 我们的初步数据有力地支持了APOC3在含有APOB100的细胞中积累的假设 脂蛋白、中密度脂蛋白(IDL)和低密度脂蛋白(LDL)使这些颗粒在T1 DM时导致动脉粥样硬化。至 验证这一假设，并为APOC3 ASO疗法预防糖尿病的临床试验奠定基础。 对于T1 DM患者的心血管疾病，我们提出了两个具体的目标。 首先，我们将确定IDL和/或LDL中的APOC3水平是否预测 匹兹堡糖尿病并发症流行病学研究，一项大型前瞻性研究。我们建议的研究是 约550名T1糖尿病患者动力充足，心血管事件发生率为30%。这些研究将利用 我们开发了最先进的方法，称为校准离子迁移率分析，它可以量化摩尔 血液中含APOB100的脂蛋白颗粒的浓度。我们的主要分析将是确定 如果i)IDL-APOC3和/或ii)LDL-APOC3预测心血管事件。 其次，我们将进行详细的代谢研究，以确定T1 DM如何改变肝脏APOC3 产量和极低密度脂蛋白周转率，以及这如何影响载脂蛋白C3在低密度脂蛋白和低密度脂蛋白中的积累 患有和不患有T1 DM的人。基于我们的小鼠研究，我们假设T1 DM促进了 肝脏APOC3产生水平损害甘油三酯脂解，导致IDL-APOC3水平升高 和/或低密度脂蛋白-载脂蛋白3。我们将用代谢因素的综合分析来补充这些分析。 (例如，体脂组成、肝脏甘油三酯、肝窦胰岛素浓度)可能调节 低密度脂蛋白、低密度脂蛋白和极低密度脂蛋白中载脂蛋白C3的浓度。 识别心血管疾病风险增加的患者应提供对心血管病发病机制的深入了解 T1 DM患者动脉粥样硬化加速。为载脂蛋白C3的临床研究奠定了基础 降低T1 DM的治疗，因为它可以针对心血管疾病高危患者。

We recently showed that serum levels of apolipoprotein C3 (APOC3) predicted incident cardiovascular disease (CVD) in CACTI, a prospective study of subjects with type 1 diabetes mellitus (T1DM). In complementary mechanistic studies, we found that reducing APOC3 levels with an antisense oligonucleotide (ASO) prevented lesion progression in a mouse model of T1DM and that apolipoprotein B (APOB)-containing lipoproteins were driving accelerated diabetic atherosclerosis. These observations are important because they strongly support the proposal that APOC3 promotes atherosclerosis in the setting of T1DM in both humans and mice. This is particularly important because ASOs to APOC3 are under investigation in humans, raising the possibility that it may be possible to reduce CVD risk in T1DM patients by lowering APOC3 levels. Our preliminary data strongly support the hypothesis that APOC3 accumulation in APOB100-containing lipoproteins, intermediate-density lipoprotein (IDL) and LDL, makes these particles atherogenic in T1DM. To test this hypothesis, and to lay the groundwork for a clinical trial of APOC3 ASO therapy in the prevention of CVD in T1DM patients, we propose two specific aims. First, we will determine whether levels of APOC3 in IDL and/or LDL predict incident CVD risk in the Pittsburgh Epidemiology of Diabetes Complications study, a large prospective study. Our proposed study is well powered with ~550 T1DM patients and >30% rate of incident CVD. These studies will take advantage of a state-of-the-art method we developedtermed calibrated ion mobility analysisthat quantifies molar concentrations of APOB100-containing lipoprotein particles in blood. Our primary analysis will be to determine if i) IDL-APOC3 and/or ii) LDL-APOC3 predict incident CVD. Second, we will perform detailed metabolic studies to determine how T1DM alters hepatic APOC3 production and VLDL turnover rates, and how this impacts the accumulation of APOC3 in LDL and IDL in humans with and without T1DM. Based on our mouse studies, we hypothesize that T1DM promotes increased levels of hepatic APOC3 production that impairs TG lipolysis, resulting in increased levels of IDL-APOC3 and/or LDL-APOC3. We will complement these analyses with comprehensive analyses of the metabolic factors (e.g., body fat composition, liver triglycerides, hepatic sinusoidal insulin concentration) that might regulate the concentration of APOC3 in LDL, IDL and VLDL. Identifying patients at increased risk for CVD should provide mechanistic insights into the pathogenesis of accelerated atherosclerosis in T1DM. Moreover, it would lay the groundwork for a clinical study of APOC3 lowering therapy in T1DM because it could target patients at high risk of CVD.