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.
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