The Metabolic Impact of Congenital Heterozygous ApoC-III Deficiency in Humans

先天性杂合 ApoC-III 缺陷对人类代谢的影响

基本信息

批准号：
8212223
负责人：
TONI I. POLLIN
金额：
$ 62.55万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-14 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212223
关键词：
Adipocytes Adipose tissue Amish Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apolipoproteins B Apolipoproteins C Area Blood Circulation Cause of Death Cell Size Clinical Complication Conflict (Psychology)Coronary Arteriosclerosis Diabetes Mellitus Drug Delivery Systems Dyslipidemias Endothelial Cells Fatty Acids Fatty acid glycerol esters Founder Effect Gene Expression General Population Genes Glucose Heart Diseases Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins High Prevalence Human Hydrolysis Hypertriglyceridemia IDL lipoproteins In Vitro Individual Inflammation Inflammatory Insulin Insulin Resistance Intervention LDL Cholesterol Lipoproteins Lead Lipids Lipolysis Lipoproteins Low-Density Lipoproteins Measures Metabolic Metabolism Methodology Muscle Mutation Non-Insulin-Dependent Diabetes Mellitus Particle Size Pathway interactions Peripheral Pharmacologic Substance Phenotype Plasma Play Production Proteins Relative (related person)Risk Role Safety Signal Pathway Therapeutic Therapeutic Intervention Time Tissues Tracer Triglycerides United States Very low density lipoprotein Visceral abdominal fat accelerated particle apolipoprotein C-III base cardiovascular disorder prevention cardiovascular risk factor coronary artery calcification cytokine disability disorder risk fatty acid oxidation feeding heart disease prevention human data inflammatory marker insulin sensitivity lipid metabolism lipoprotein lipase null mutation oxidation particle public health relevance residence respiratory response stable isotope subcutaneous uptake very low density lipoprotein triglyceride

项目摘要

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the leading cause of death in the United States and is a major complication of type 2 diabetes (T2DM). Dyslipidemia, characterized by elevated low density lipoprotein cholesterol (LDL-C) and triglyceride levels and decreased high density lipoprotein cholesterol (HDL-C) levels, is associated with increased risk of CAD. The high TG/ low HDL-C phenotype is particularly prevalent in individuals with insulin resistance or T2DM. Apolipoprotein C-III (apoC-III), an 8.8 kDa protein component of both triglyceride-rich lipoproteins (TRLs) and HDL particles, inhibits lipoprotein lipase activity and hepatic uptake of TRLs. ApoC-III may also enhance very low density lipoprotein (VLDL) assembly and secretion, but the findings on this based on animal models and human studies are conflicting. In addition, apoC-III activates inflammatory signaling pathways, a cardiovascular risk factor of emerging importance. We recently provided evidence that apoC-III deficiency is cardioprotective by identifying a null mutation found in ~5% of the Lancaster Old Order Amish that reduces apoC-III levels by ~50% and confers favorable lipid profiles and less coronary calcification. The mutation appears rare or absent in the general population but has reached a relatively high prevalence in the Amish by a founder effect. While these recent findings strongly implicate direct apoC- III lowering as a promising therapeutic intervention, the enhanced lipolytic activity conferred by apoC-III reduction could theoretically promote disease risk by increasing visceral and muscle fat stores, which would be expected to promote insulin resistance. Alternatively, the enhanced flux of fatty acids into peripheral tissues may promote sufficient compensatory increases in fatty acid oxidation to make direct lowering of apoC-III levels a suitable target in the prevention of cardiovascular disease in insulin resistant individuals. To enhance our understanding of the metabolic effects of decreased availability of apoC-III and the role apoC-III plays in VLDL secretion in humans, we are proposing to compare individuals with heterozygous apoC-III deficiency to their non-deficient relatives to (1) evaluate the effect of apoC-III defiency on glucose and insulin metabolism and fat distribution; (2) evaluate the effect of apoC-III defiency on lipid and lipoprotein turnover; and (3) evaluate the effect of apoC-III deficiency on fat cells and their function. PUBLIC HEALTH RELEVANCE: Heart disease is a leading cause of death and disability in the United States. People who have an inborn deficiency of a protein called apoC-III appear to have a reduced risk of developing heart disease, suggesting that reducing the amount of apoC-III made in other individuals could be a useful treatment or prevention for heart disease, especially in people with diabetes. This project will look more closely at the effects of the deficiency on human metabolism to better understand the function of the apoC-III protein and its potential as a drug target.

描述（由申请人提供）：冠状动脉疾病 (CAD) 是美国的首要死因，也是 2 型糖尿病 (T2DM) 的主要并发症。血脂异常的特征是低密度脂蛋白胆固醇 (LDL-C) 和甘油三酯水平升高以及高密度脂蛋白胆固醇 (HDL-C) 水平降低，与 CAD 风险增加相关。高 TG/低 HDL-C 表型在胰岛素抵抗或 T2DM 个体中尤其普遍。载脂蛋白 C-III (apoC-III) 是富含甘油三酯的脂蛋白 (TRL) 和 HDL 颗粒的 8.8 kDa 蛋白质成分，可抑制脂蛋白脂肪酶活性和 TRL 的肝脏摄取。 ApoC-III 还可能增强极低密度脂蛋白 (VLDL) 的组装和分泌，但基于动物模型和人体研究的结果是相互矛盾的。此外，apoC-III 还可激活炎症信号通路，这是一种日益重要的心血管危险因素。我们最近通过鉴定约 5% 的兰卡斯特旧秩序阿米什人中发现的无效突变，提供了证据表明 apoC-III 缺乏症具有心脏保护作用，该突变使 apoC-III 水平降低约 50%，并赋予良好的血脂特征和较少的冠状动脉钙化。这种突变在普通人群中似乎很少见或不存在，但由于创始人效应，在阿米什人中已经达到相对较高的患病率。虽然这些最近的发现强烈表明直接降低 apoC-III 是一种有前途的治疗干预措施，但 apoC-III 降低所带来的增强的脂肪分解活性理论上可能会通过增加内脏和肌肉脂肪储存来增加疾病风险，预计这会促进胰岛素抵抗。或者，脂肪酸进入外周组织的流量增加可以促进脂肪酸氧化的充分代偿性增加，从而使直接降低apoC-III水平成为预防胰岛素抵抗个体心血管疾病的合适目标。为了加深我们对 apoC-III 可用性降低的代谢影响以及 apoC-III 在人类 VLDL 分泌中所起的作用的理解，我们建议将杂合子 apoC-III 缺陷的个体与其非缺陷亲属进行比较（1）评估 apoC-III 缺乏对葡萄糖和胰岛素代谢以及脂肪分布的影响； (2)评估apoC-III缺乏对脂质和脂蛋白周转的影响； (3)评估apoC-III缺陷对脂肪细胞及其功能的影响。公共卫生相关性：心脏病是美国死亡和残疾的主要原因。先天性缺乏 apoC-III 蛋白质的人患心脏病的风险似乎较低，这表明减少其他人体内产生的 apoC-III 的量可能是治疗或预防心脏病的有效方法，尤其是在心脏病患者中。患有糖尿病的人。该项目将更仔细地研究缺陷对人体新陈代谢的影响，以更好地了解 apoC-III 蛋白的功能及其作为药物靶点的潜力。