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

载脂蛋白 B100 脂蛋白的载脂蛋白 C3 负载与 1 型糖尿病患者的心血管疾病

• 批准号: 10546500
• 负责人: JAY W HEINECKE
• 金额: $ 82.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-05 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546500
• 关键词: Acceleration; Address; Age; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Apolipoproteins; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Binding; Blood; Blood Pressure; Body fat; Body mass index; Calibration; Cardiovascular Diseases; Cardiovascular system; Clinical Research; Clinical Trials; Collaborations; Complement; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Coronary artery; Data; Diabetes Mellitus; Diabetic mouse; Endothelial Cells; Epidemiology; Genetic Complementation Test; Glucose; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hyperglycemia; Hypertriglyceridemia; IDL lipoproteins; Impairment; Incidence; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Isotopes; LDL Cholesterol Lipoproteins; Lesion; Lipids; Lipolysis; Lipoproteins; Liver; Low-Density Lipoproteins; Metabolic; Metabolic Clearance Rate; Methods; Mus; Myeloid Cells; Normal Range; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Production; Prospective Studies; Proteins; Proteomics; Research Design; Risk; Risk Factors; Sampling; Series; Serum; Smooth Muscle Myocytes; Study Subject; Testing; Triglycerides; Universities; Very low density lipoprotein; Washington; Work; cardiovascular disorder prevention; cardiovascular disorder risk; coronary artery calcium; diabetic; experimental study; follow-up; glycemic control; high risk; insight; ion mobility; metabolic abnormality assessment; mouse model; non-diabetic; novel strategies; particle; premature; prevent; prospective; risk prediction; sex; stable isotope; therapeutic target

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.

我们最近表明，载脂蛋白C3（APOC3）的血清水平预测了心血管疾病 （CVD）在仙人掌中，对1型糖尿病（T1DM）的受试者的前瞻性研究。在完成 机械研究，我们发现使用反义寡核苷酸（ASO）降低APOC3水平 T1DM的小鼠模型和载脂蛋白B（APOB）含脂蛋白的病变进展为 驱动加速的糖尿病动脉粥样硬化。这些观察很重要，因为它们强烈支持 在人类和小鼠的T1DM环境中，APOC3促进动脉粥样硬化的提议。这是 特别重要，因为在人类中正在调查ASOS对APOC3，这增加了它的可能性 通过降低APOC3水平，可能有可能降低T1DM患者的CVD风险。 我们的初步数据强烈支持以下假设：ApoC3在含ApoB100的 脂蛋白，中等密度的脂蛋白（IDL）和LDL使这些颗粒在T1DM中使这些颗粒动脉粥样硬化。到 检验该假设，并为APOC3 ASO治疗的临床试验奠定基础 CVD在T1DM患者中，我们提出了两个具体目标。 首先，我们将确定IDL和/或LDL中的APOC3水平是否预测事件CVD风险 匹兹堡糖尿病并发症研究的流行病学研究，一项大型前瞻性研究。我们提出的研究是 由约550 T1DM患者提供良好的功率，入射CVD率> 30％。这些研究将利用 最先进的方法我们开发了校准的离子迁移率分析量化摩尔 血液中含有APOB100的脂蛋白颗粒的浓度。我们的主要分析是确定 如果i）IDL-APOC3和/或II）LDL-APOC3预测事件CVD。 其次，我们将进行详细的代谢研究，以确定T1DM如何改变肝APOC3 生产和VLDL周转率，以及这如何影响apoc3在LDL和IDL中的积累 有和没有T1DM的人。根据我们的小鼠研究，我们假设T1DM促进了增加 损伤TG脂解的肝APOC3水平，导致IDL-APOC3水平升高 和/或LDL-APOC3。我们将通过对代谢因素进行全面分析来完成这些分析 （例如，体内脂肪组成，肝甘油三酸酯，肝正正弦胰岛素浓度），可能调节 LDL，IDL和VLDL中的ApoC3浓度。 确定患有CVD风险增加的患者应为机械洞察力提供有关的发病机理 T1DM中的动脉粥样硬化加速。此外，它将为APOC3的临床研究奠定基础 降低T1DM治疗，因为它可以针对具有CVD高风险的患者。