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: 10370044
• 负责人: JAY W HEINECKE
• 金额: $ 86.23万
• 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/10370044
• 关键词: Address; Age; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Apolipoproteins; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood; Blood Pressure; Body fat; Body mass index; 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; 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; base; cardiovascular disorder prevention; cardiovascular disorder risk; coronary artery calcium; diabetic; experimental study; follow-up; glycemic control; high risk; insight; ion mobility; low density lipoprotein triglyceride; 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) 的血清水平可预测心血管疾病的发生 (CVD) 在 CACTI 中，这是一项针对 1 型糖尿病 (T1DM) 受试者的前瞻性研究。互补中 机制研究中，我们发现用反义寡核苷酸 (ASO) 降低 APOC3 水平可以防止 T1DM 小鼠模型中的病变进展以及含载脂蛋白 B (APOB) 的脂蛋白 加速糖尿病动脉粥样硬化。这些观察很重要，因为它们强烈支持 APOC3 在人类和小鼠的 T1DM 环境中促进动脉粥样硬化的提议。这是 特别重要的是，因为 APOC3 的 ASO 正在人体中进行研究，这增加了它的可能性 通过降低 APOC3 水平可能会降低 T1DM 患者的 CVD 风险。 我们的初步数据强烈支持以下假设：APOC3 在含有 APOB100 的细胞中积累 脂蛋白、中密度脂蛋白 (IDL) 和 LDL，使这些颗粒在 T1DM 中导致动脉粥样硬化。到 检验这一假设，并为 APOC3 ASO 疗法预防疾病的临床试验奠定基础 针对 T1DM 患者的 CVD，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 水平是否可以预测心血管疾病的风险。 匹兹堡糖尿病并发症流行病学研究，一项大型前瞻性研究。我们提出的研究是 动力充足，约有 550 名 T1DM 患者，CVD 发生率 >30%。这些研究将利用 我们开发的最先进的方法——称为校准离子淌度分析——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 可以预测 CVD 事件。 其次，我们将进行详细的代谢研究，以确定 T1DM 如何改变肝脏 APOC3 生产和 VLDL 周转率，以及这如何影响 LDL 和 IDL 中 APOC3 的积累 患有和不患有 T1DM 的人。根据我们的小鼠研究，我们假设 T1DM 会促进 肝脏 APOC3 的产生水平会损害 TG 脂解作用，导致 IDL-APOC3 水平增加 和/或 LDL-APOC3。我们将通过对代谢因素的综合分析来补充这些分析 （例如身体脂肪成分、肝脏甘油三酯、肝窦胰岛素浓度）可能调节 LDL、IDL 和 VLDL 中 APOC3 的浓度。 识别 CVD 风险增加的患者应为 CVD 的发病机制提供机制见解 T1DM 加速动脉粥样硬化。此外，这将为 APOC3 的临床研究奠定基础 减少 T1DM 的治疗，因为它可以针对心血管疾病高风险患者。