AGEPC--A POTENT LIPID BIOCHEMICAL MEDIATOR IN LIVER

雅培(1-0-Alky1-2-acetyl-sn-glycero-3-phosphocholine)是一家强大的、 哺乳动物肝脏中的类脂类介体。我们有 证明了在摩尔基础上，AGEPC是最有效的 已知的血管收缩、糖原分解激动剂的一半最大 反应发生在10“10到10-11米。肝脏AGEPC效应是 受体介导的，是钙敏感的，涉及邻近的二硫醇， 被B-肾上腺素能激动剂抑制，需要完整的 脉管系统。此外，AGEPC是由肝脏灌流合成的 用诸如热聚集的免疫球蛋白等颗粒物质进行挑战， 酵母多糖或乳胶包衣微球。AGEPC的受体为 定位于门静脉小静脉的窦状细胞。 AGEPC具有显著的血糖调节作用。 完好无损的动物。在拟议的资助期内，研究将 设计a)阐明AGEPC涉及的调控机制 大鼠肝脏和原代肝脏的合成和分解代谢 肝脏来源细胞的培养，如枯否细胞、内皮细胞和 实质细胞：b)确定AGEPC的致病机制 它在这个肝细胞系统中的生物学效应；以及：c) 表征潜在的调解人之间的协同或拮抗 AGEPC和其他调解人。拟议研究的一个主要重点 将对两者进行分离、表征和结构证明 血小板活化因子活性的抑制剂已经被 在肝脏中发现。其中一种抑制性化合物是一种脂肪 另一种是乙醇胺磷酸甘油酯。 曾刻画了抑制AGEPC的机制(S) 这些抑制反应及其生理意义 我们将探索物质。我们的整个研究项目是 旨在描述一种独特的、具有重要生理意义的 细胞间信令过程，在 成分网状内皮细胞和实质细胞 肝脏的。我们的论点是这种类型的信号 系统没有参与日常的糖调节事件 正常个体，相当于类金丝雀样介质刺激的肝脏 糖原分解在高血压患者的高血糖反应中最重要 急性过敏、内毒素血症或炎症时的肝脏 反应。

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.