METABOLIC RELATIONSHIP AMONG TRIGLYCERIDE-RICH LIPOPROTEINS AND HDLS

富含甘油三酯的脂蛋白和 HDLS 之间的代谢关系

• 批准号: 3844094
• 负责人: WOLFGANG PATSCH
• 金额: --
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3844094
• 关键词: analytical ultracentrifugation; apolipoproteins; blood lipid; blood lipoprotein; blood lipoprotein metabolism; cholesterol; coronary artery; coronary disorder; family genetics; fatty acids; fibroblasts; gas chromatography; gene expression; glycosylation; high density lipoproteins; human subject; hyperlipidemia; hypertriglyceridemia; immunoaffinity chromatography; insulin sensitivity /resistance; lipase; lipoprotein lipase; liver cells; macrophage; monoclonal antibody; steroid metabolism; transcription factor; vascular endothelium

There exists a close inverse relationship between the plasma levels of triglycerides (TG) and HDL-cholesterol (HDL-chol) suggesting that the metabolism of one of these lipids affects that of the other. By all the available evidence, it is the metabolism of triglyceride-rich lipoproteins (TGRL) which controls association between HDL-chol and not vice versa. Therefore, the powerful negative association between HDL-chol and coronary artery disease (CAD) may in reality be a positive relationship between CAD and the metabolism of TGRL. Rapid catabolism of TGRL, as reflected in modest postprandial lipemia, limits the time available for their enrichment with cholesteryl esters and provides surface phospholipids from nascent TGRL required for the anabolic formation of HDL2. By contrast, pronounced alimentary lipemia leads to cholesteryl ester enrichment of TGRL and accelerates the catabolism of HDL. The aim of this proposal is to test the above hypotheses through three major objectives: i)to separate postprandial lipoproteins of hepatic and intestinal origins at various time points of the alimentary cycle and characterize their physiochemical properties, lipid and apoprotein composition, and to study their ability to affect the metabolism of fibroblasts, macrophages and liver and endothelial cells in culture; ii)to identify HDL subfractions which are essential for or indicative of defined metabolic events of TGRL in vivo; to develop and apply an in vitro model system that allows identification of factors which determine the rates of conversion of HDL3 subfractions into HDL2 and vice versa; to determine the effects of these interconversions on cellular cholesterol metabolism and cholesterol routing among lipoproteins; iii)to measure the contribution of genetic factors to postprandial lipid metabolism in family studies and determine their co-aggregation with CAD and candidate genes involved in lipid metabolism; to study the relationship of insulin resistance and alimentary lipemia in subjects before and after therapeutic interventions known to enhance insulin sensitivity, in order to identify a potential role of trans-activating factors in the expression of genes relevant for the metabolism of TGRL. These studies represent a logical extension of our previous work on lipoprotein metabolism, postprandial lipemia and its association with CAD and should elucidate the mechanisms underlying the relationships among CAD, HDL-chol, and plasma triglycerides.

在血浆中， 甘油三酯（TG）和高密度脂蛋白胆固醇（HDL-chol）表明， 其中一种脂质的代谢影响另一种脂质的代谢。 由所有 现有的证据表明，它是代谢富含磷脂酰肌醇的脂蛋白 （TGRL），其控制HDL-胆固醇之间的关联，而不是反之亦然。 因此，HDL-chol与冠状动脉粥样硬化之间的强负相关性 动脉疾病（CAD）实际上可能与CAD之间存在正相关关系， 和TGRL的代谢。 TGRL的快速催化剂，如 适度的餐后脂血症，限制了可用于其富集的时间 与胆固醇酯，并提供表面磷脂从新生的 HDL 2合成代谢形成所需的TGRL。 相比之下， 营养性脂血导致TGRL的胆固醇酯富集， 加速HDL的分解。 本提案的目的是测试 通过三个主要目标实现上述假设： i）分离肝和肠来源的餐后脂蛋白 在消化周期的不同时间点，并表征其 理化性质，脂质和载脂蛋白组成，并研究 它们影响成纤维细胞、巨噬细胞和 培养的肝细胞和内皮细胞; ii）鉴定HDL亚组分，所述HDL亚组分对于以下各项是必需的或指示以下各项 TGRL在体内的定义的代谢事件;开发和应用体外 一个模型系统，允许识别决定 HDL 3亚组分转化为HDL 2的速率，反之亦然; 确定这些相互转化对细胞胆固醇的影响 脂蛋白之间的代谢和胆固醇路由; iii）测量遗传因素对餐后脂质的贡献 代谢的家族研究，并确定其与CAD的共聚集 和参与脂质代谢的候选基因;研究它们之间的关系， 胰岛素抵抗和营养性脂血症的研究 已知可增强胰岛素敏感性的治疗干预， 确定反式激活因子在以下表达中的潜在作用： 与TGRL代谢相关的基因。 这些研究表明， 我们先前关于脂蛋白代谢的工作的逻辑延伸， 餐后脂血症及其与CAD的关系，并应阐明 CAD、HDL-chol和血浆之间关系的潜在机制 甘油三酯