AGEPC--A POTENT LIPID BIOCHEMICAL MEDIATOR IN LIVER

1-O-烷基-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育素介质。 我们有 证明在摩尔基础上AGEPC是最有效的 血管收缩，糖原分解激动剂，已知在半最大 反应发生在10 - 10至10-11 M。 肝脏AGEPC效应是 受体介导的，是钙敏感的，涉及邻位二硫醇， 被β-肾上腺素能激动剂抑制，需要完整的 脉管系统 此外，AGEPC由灌注的肝脏合成 用颗粒物质如热聚集的IgG攻击， 酵母聚糖或胶乳涂覆的微球。 AGEPC的受体是 位于门静脉小静脉的窦状细胞上。 AGEPC的实质性葡萄糖调节作用可以在 完整的动物。 在建议的资助期内， 设计a）阐明AGEPC中涉及的调控机制 在灌注大鼠肝脏和原代大鼠肝脏中的合成和催化 肝衍生细胞的培养物，例如，Kupffer，内皮和 实质细胞：B）定义AGEPC引起 其在该肝细胞系统中的生物学效应;以及：c） 表征潜在介质之间的协同作用或拮抗作用 AGEPC和其他调解人。 拟议研究的一个主要重点是 将是两个分离，表征和结构证明 血小板活化因子活性的抑制剂， 在肝脏中发现。 这些抑制化合物之一是脂肪酸 类酸化合物和另一种乙醇胺磷酸甘油酯。 一旦表征AGEPC抑制机制 反应和生理重要性，这些抑制 物质将被探索。 我们的整个研究项目 旨在描述一种独特的、生理上重要的 细胞间的信号传递过程， 网状内皮细胞和实质细胞 肝脏的 我们认为这种信号 系统不参与日常血糖调节事件， 正常个体，而不是自体激素介导刺激的肝 糖原分解是最重要的高血糖反应， 在急性过敏反应、内毒素血症或炎性 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.