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

• 批准号: 8402860
• 负责人: TONI I. POLLIN
• 金额: $ 58.17万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/8402860
• 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 Targeting; 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

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.

描述（由申请人提供）：冠状动脉疾病（CAD）是美国死亡的主要原因，是2型糖尿病（T2DM）的主要并发症。血脂异常，其特征是低密度脂蛋白胆固醇（LDL-C）和甘油三酸酯水平升高，并且高密度脂蛋白胆固醇（HDL-C）水平降低与CAD风险增加有关。高TG/低HDL-C表型在胰岛素抵抗或T2DM的个体中尤为普遍。载脂蛋白C-III（APOC-III）是富含甘油三酸酯的脂蛋白（TRL）和HDL颗粒的8.8 kDa蛋白成分，可抑制脂蛋白脂肪酶活性和TRL肝摄取。 APOC-III还可能增强非常低的密度脂蛋白（VLDL）组装和分泌，但是基于动物模型和人类研究的结果是矛盾的。此外，APOC-III激活炎症信号通路，这是新兴重要性的心血管风险因素。我们最近提供了证据表明，APOC-III缺乏症是心脏保护性的，通过识别约5％的兰开斯特旧秩序Amish的无效突变，该突变将APOC-III III水平降低了约50％，并赋予了有利的脂质曲线和更少的冠状动脉钙化。该突变在普通人群中似乎很少或不存在，但通过创始人效应，阿米什人的患病率相对较高。尽管这些最近的发现强烈暗示了直接的APOC-III降低是一种有希望的治疗性干预措施，但APOC-III减少赋予的脂解活性的增强可以通过增加内脏和肌肉脂肪储存来促进疾病的风险，这可以预期可以促进胰岛素抵抗。另外，脂肪酸向周围组织的通量增强可能会促进脂肪酸氧化的足够补偿性增加，以使apoc-III水平直接降低抗胰岛素耐药性个体中心血管疾病的合适靶标。为了增强我们对apoc-III可用性降低的代谢效应的理解以及apoc-iii在人类中的VLDL分泌中所发挥的作用，我们提议比较患有杂合的apoc-iii障碍的人与非缺陷型相关词与（1）评估apoc-iiii defical and glucose and Insulin getulin getulin getulin getulin getulin getulin getabism and Intabism的影响； （2）评估APOC-III缺乏症对脂质和脂蛋白更新的影响； （3）评估APOC-III缺乏对脂肪细胞及其功能的影响。