AGEPC--A POTENT LIPID BIOCHEMICAL MEDIATOR IN LIVER

AGEPC--肝脏中有效的脂质生化介质

• 批准号: 3231951
• 负责人: DONALD J HANAHAN
• 金额: $ 24.49万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3231951
• 关键词: calcium; epinephrine; gel electrophoresis; glucagon; glucose metabolism; glycogenolysis; laboratory rat; lipid metabolism; liver cells; liver metabolism; mass spectrometry; perfusion; phosphatidylinositols; platelet activating factor; platelet aggregation inhibitors; receptor; tissue /cell culture; vasoconstrictors

1-0-Alky1-2-acetyl-sn-glycero-3-phosphocholine (AGEPC) is a potent, lipid autacoid mediator in the mammalian liver. We have demonstrated that on a molar basis AGEPC is the most potent vasoconstrictive, glycogenolytic agonist known in that half maximal responses occur at 10"10 to 10-11 M. Hepatic AGEPC effects are receptor-mediated, are calcium sensitive, involve vicinal dithiols, are inhibited by B-adrenergic agonists and require an intact vasculature. Moreover, AGEPC is synthesized by perfused livers challenged with particulate substances such as heat aggregated IgG, zymosan or latex-coated microspheres. Receptors for AGEPC are localized on sinusoidal cells of the small portal venules. Substantial glucoregulatory effects of AGEPC can be observed in the intact animal. During the proposed funding period studies will be designed a) to elucidate regulatory mechanisms involved in AGEPC synthesis and catabolism in the perfused rat liver and in primary cultures of liver derived cells, e.g., Kupffer, endothelial and parenchymal cells: b) to define mechanisms by which AGEPC causes its biological effects in this hepatocellular system; and: c) to characterize potential mediator synergism or antagonism between AGEPC and other mediators. A major focus of the proposed research will be the isolation, characterization and structure proof of two inhibitors of platelet activating factor activity which have been found in the liver. One of these inhibitory compounds is a fatty acid-like compound and the other an ethanolamine phosphoglyceride. Once characterized the mechanism(s) of inhibition of AGEPC responses and the physiological importance of these inhibitory substances will be explored. Our entire research program is designed to characterize a unique and physiologically important intercellular signaling process that transfers information between the component reticuloendothelial cells and the parenchymal cells of the liver. It is our contention that this type of signaling system is not involved in day-to-day glucoregulatory events in the normal individual, rather autacoid mediator-stimulated hepatic glycogenolysis is most important in the hyperglycemic response of the liver during acute anaphylaxis, endotoxemia or inflammatory reactions.

1-0-Alky1-2-乙酰基-sn-甘油-3-磷酸胆碱 (AGEPC) 是一种有效的、 哺乳动物肝脏中的脂质自体介质。 我们有 证明以摩尔计 AGEPC 是最有效的 已知半最大血管收缩、糖原分解激动剂 反应发生在 10"10 至 10-11 M。肝脏 AGEPC 效应是 受体介导的，钙敏感的，涉及邻位二硫醇， 被B-肾上腺素能激动剂抑制并需要完整的 脉管系统。 此外，AGEPC是由灌注肝脏合成的 受到颗粒物质的挑战，例如热聚集的 IgG， 酵母聚糖或乳胶包被的微球。 AGEPC 的受体是 位于小门静脉的正弦细胞上。 AGEPC 的显着葡萄糖调节作用可以在 完整的动物。 在拟议的资助期内，研究将 旨在 a) 阐明 AGEPC 涉及的调控机制 灌注大鼠肝脏和原代肝脏中的合成和分解代谢 肝源性细胞培养物，例如枯否细胞、内皮细胞和 实质细胞：b) 定义 AGEPC 引起的机制 它在肝细胞系统中的生物学效应；以及：c) 至 描述潜在介体之间的协同或拮抗作用 AGEPC 和其他调解员。 拟议研究的一个主要焦点 将是两个的隔离、表征和结构证明 血小板活化因子活性抑制剂 发现于肝脏。 这些抑制性化合物之一是脂肪 一种酸类化合物，另一种是乙醇胺磷酸甘油酯。 一旦确定了 AGEPC 的抑制机制 反应以及这些抑制的生理重要性 将探索物质。 我们的整个研究计划是 旨在表征独特且具有生理重要性的 细胞间传递信息的信号传导过程 网状内皮细胞和实质细胞的成分 肝脏的。 我们认为这种类型的信号 系统不参与日常的血糖调节事件 正常个体，而非自体介质刺激的肝脏 糖原分解在高血糖反应中最重要 急性过敏反应、内毒素血症或炎症期间的肝脏 反应。