CONTROL OF ICOSANOID PRECURSOR FATTY ACID METABOLISM

二十烷酸前体脂肪酸代谢的控制

• 批准号: 3236378
• 负责人: Michael Laposata
• 金额: $ 13.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3236378
• 关键词: Tangier disease; arachidonate; blood lipoprotein transport; eicosanoid metabolism; fatty acid metabolism; fatty acid transport; human subject; intracellular transport; radiotracer

Icosanoids are potent biologic mediators derived from a specifically designated pool of fatty acids known as icosanoid-precursor fatty acids. Inhibition of icosanoid production by aspirin has been shown to reduce inflammation and the risk of thrombosis leading to stroke and myocardial infarction. For the last 5 years our laboratory has been investigating the molecular mechanisms by which arachidonate, the principal icosanoid precursor fatty acid, is converted to icosanoids, with the intention of identifying new regulatory steps which might be susceptible to pharmacologic intervention. In an effort to continue this work, this proposal also describes experiments intended to increase our understanding of the molecular events in the conversion of arachidonate and other icosanoid-precursor fatty acids to icosanoids. However, where our previous work focused exclusively on cellular fatty acid metabolism, the goals of the proposed work are to determine 1) the molecular mechanisms by which fatty acids are delivered to cells from triacylglycerol, phospholipids, and cholesterol esters in lipoproteins and from the nonesterified fatty acid pool bound to albumin and 2) how the particular route of delivery of fatty acid to cells effects its distribution within membranes of the cell and its metabolic fate inside the cells. Our first major objective is to determine which fatty acid-containing moieties within lipoproteins containing icosanoid precursor fatty acids actually deliver these fatty acids to cells (endothelial cells, platelets, and Hep G2 cells). Within this first objective, we will compare delivery of fatty acids to cells from the different lipoprotein moieties vs free fatty acid bound to albumin. Our second major objective is to determine whether the fate of icosanoid precursor fatty acids in cells, in terms of subcellular distribution (in Hep G2 cells), availability for icosanoid production (by endothelial cells and platelets), or packaging into newly synthesized lipoproteins (by Hep G2 cells), is dependent on the moiety which delivers the fatty acid to the cell. This series of aims, a logical extension of our previous work, will provide missing details on the molecular events by which icosanoid precursor fatty acids are transported in the plasma and delivered to cells.

二十烷酸是源自特定物质的有效生物介质 被称为二十烷酸前体脂肪酸的指定脂肪酸库。 阿司匹林抑制二十烷酸的产生已被证明可以减少 炎症和血栓形成导致中风和心肌梗塞的风险 梗塞。 过去 5 年我们的实验室一直在研究 主要二十烷酸花生四烯酸的分子机制 前体脂肪酸，转化为二十烷酸，目的是 确定可能容易受到影响的新监管措施 药物干预。 为了继续这项工作，本 提案还描述了旨在增加我们的实验 了解花生四烯酸转化中的分子事件 和其他二十烷酸的前体脂肪酸。 然而，在哪里 我们之前的工作专门关注细胞脂肪酸代谢， 拟议工作的目标是确定 1) 分子 脂肪酸输送至细胞的机制 脂蛋白中的三酰甘油、磷脂和胆固醇酯 以及来自与白蛋白结合的非酯化脂肪酸库以及2)如何 脂肪酸输送到细胞的特定途径会影响其 细胞膜内的分布及其内部的代谢命运 细胞。 我们的首要目标是确定哪种脂肪 含有二十烷酸的脂蛋白内的含酸部分 前体脂肪酸实际上将这些脂肪酸传递到细胞 （内皮细胞、血小板和 Hep G2 细胞）。 在这第一 目的，我们将比较脂肪酸向细胞的输送 不同的脂蛋白部分与与白蛋白结合的游离脂肪酸。 我们的 第二个主要目标是确定二十烷酸的命运是否 细胞中的前体脂肪酸，就亚细胞分布而言（在 Hep G2 细胞），可用于生产二十烷酸（通过内皮细胞 细胞和血小板），或包装成新合成的脂蛋白 （由 Hep G2 细胞），取决于传递脂肪的部分 酸进入细胞。 这一系列目标是我们的逻辑延伸 之前的工作，将提供分子事件缺失的细节 哪些二十烷酸前体脂肪酸在血浆中转运 递送至细胞。