CONTROL OF ICOSANOID PRECURSOR FATTY ACID METABOLISM

二十烷酸前体脂肪酸代谢的控制

• 批准号: 3236376
• 负责人: Michael Laposata
• 金额: $ 12.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3236376
• 关键词: acid thiol ligase; acyl coA; arachidonate; eicosanoid metabolism; fatty acid metabolism; human tissue; linolenate; phospholipids; prostaglandin E; tissue /cell culture; vascular endothelium

This is a proposal to 1) study the regulation of arachidonoyl-CoA synthesis in mammalian cells, and 2) attempt to identify the pool of arachidonoyl-CoA which is esterified into phospholipid and then released for production of icosanoids. We have recently demonstrated that icosanoid production in cultured cells can be controlled at a step prior to arachidonate release from phospholipid, namely, at the point of arachidonoyl-CoA formation. This represents a newly discovered option for the control of icosanoid formation. Icosanoids are implicated in a multitude of disease processes including atherosclerosis and thrombosis leading to myocardial infarction and stroke and autoimmune disease, produced by uncontrolled inflammation. We have recently shown, using the prostaglandin E2 producing cell line HSDM1C1 and several cell lines unique in various aspects of icosanoid precursor fatty acid metabolism, that arachidonoyl-CoA formation in mammalian cells involves three metabolic pathways: 1) the Delta6 desaturase/elongase/ Delta5 desaturase pathway, 2) the non-specific long chain acyl-CoA synthetase, and 3) arachidonoyl-CoA synthetase. Furthermore, we have been able to alter the flux through these pathways. Using our cultured cell lines, we propose to study the regulation of each of the three pathways leading to arachidonoyl-CoA formation. Specifically, we plan to study: 1) the induction of Delta6 desaturase and control of induction by fatty acid, 2) the identification of a factor(s) in an extract of horse serum which we have shown controls arachidonoyl-CoA synthetase activity, and 3) the induction of non-specific acyl-CoA synthetase activity by micromolar concentrations of various fatty acids. We will also investigate the capacity of arachidonate derived from its precursor fatty acids to enter the pool of arachidonoyl-CoA destined for prostaglandin E2 synthesis. The information from our studies on arachidonoyl-CoA synthesis, a new control point for icosanoid formation, could ultimately have a significant impact on icosanoid-mediated disease.

本提案旨在 1) 研究花生四烯酰辅酶 A 合成的调控 在哺乳动物细胞中，2) 尝试鉴定花生四烯酰辅酶 A 库 它被酯化成磷脂，然后释放以生产 二十烷酸。 我们最近证明二十烷酸的生产 可以在花生四烯酸释放之前的步骤中控制培养的细胞 来自磷脂，即在花生四烯酰辅酶A形成时。 这代表了一种新发现的控制二十烷酸的选择 形成。 二十烷酸与多种疾病过程有关 包括导致心肌梗塞的动脉粥样硬化和血栓形成 以及由不受控制的炎症引起的中风和自身免疫性疾病。 我们最近证明，使用产生前列腺素 E2 的细胞系 HSDM1C1 和几种在二十烷酸各方面独特的细胞系 前体脂肪酸代谢，即花生四烯酰辅酶A的形成 哺乳动物细胞涉及三种代谢途径：1) Delta6 去饱和酶/延伸酶/Delta5去饱和酶途径，2)非特异性长 链酰基辅酶A合成酶，和3)花生四烯酰基辅酶A合成酶。 此外，我们已经能够改变通过这些途径的通量。 我们建议使用我们培养的细胞系来研究每个细胞的调节 导致花生四烯酰辅酶A形成的三种途径。 具体来说， 我们计划研究：1）Delta6去饱和酶的诱导和控制 脂肪酸诱导，2) 提取物中因子的鉴定 我们已经证明马血清控制花生四烯酰辅酶A合成酶 活性，以及​​ 3) 诱导非特异性酰基辅酶 A 合成酶活性 通过各种脂肪酸的微摩尔浓度。 我们还将 研究源自其前体脂肪的花生四烯酸的能力 酸进入花生四烯酰辅酶 A 池，生成前列腺素 E2 合成。 我们对花生四烯酰辅酶A合成的研究信息， 二十烷酸形成的新控制点，最终可能会产生 对二十烷酸介导的疾病有显着影响。