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.

我们最近发现血清载脂蛋白C3 （APOC3）水平可以预测心血管疾病的发生