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: 3736263
• 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/3736263
• 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.

两种药物的血浆水平之间存在密切的负相关关系 甘油三酯(TG)和高密度脂蛋白-胆固醇(HDL-CHOL)表明 其中一种脂类的新陈代谢会影响另一种。由所有的 现有证据表明，它是富含甘油三酯的脂蛋白的代谢 (TGRL)，控制高密度脂蛋白-胆固醇之间的关联，而不是反之亦然。 因此，高密度脂蛋白-胆固醇与冠状动脉 动脉疾病(CAD)实际上可能是CAD与 和TGRL的代谢。TGRL的快速分解代谢，反映在 轻度餐后脂血症，限制了可用于补充它们的时间 含有胆固醇酯，并从新生提供表面磷脂 HDL2合成代谢所需的TGRL。相比之下，发音为 消化性血脂导致TGRL和TGRL的胆固醇酯积累 加速高密度脂蛋白的分解代谢。这项提议的目的是测试 以上假设通过三大目标实现： I)分离源自肝脏和肠道的餐后脂蛋白 在食物循环的不同时间点上，并描述它们的特征 理化性质、脂类和载脂蛋白组成，并进行研究 它们能够影响成纤维细胞、巨噬细胞和 培养中的肝脏和内皮细胞； 二)确定高密度脂蛋白亚组分对以下各项是必要的或指示的 确定TGRL在体内的代谢事件；体外开发和应用一种 一种模型系统，允许识别决定 HDL3亚组分转化为HDL2的速率； 确定这些相互转换对细胞胆固醇的影响 脂蛋白之间的代谢和胆固醇的传递； 三)衡量遗传因素对餐后血脂的影响 家族性研究中的代谢及其与冠心病的协同聚集性 和参与脂类代谢的候选基因；研究它们之间的关系 受试者治疗前后胰岛素抵抗和消化性血脂的变化 已知的可提高胰岛素敏感性的治疗干预措施，以 确定反式激活因子在基因表达中的潜在作用 与TGRL代谢相关的基因。这些研究代表了一种 我们之前关于脂蛋白新陈代谢的工作的合理扩展， 餐后血脂及其与冠心病的相关性，并应阐明 冠心病、高密度脂蛋白-胆固醇和血浆之间关系的潜在机制 甘油三酯。