REGULATORY MECHANISMS IN HEPATIC METABOLISM

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The objective of the proposed research project is to investigate the mechanistic details of important inter- and intracellular regulatory signaling systems operative in the mammalian liver during acute pathophysiological situations. Such signaling system(s) will be characterized in the intact perfused rat liver and in primary cultures of liver-derived cells, i.e., parenchymal, Kupffer and endothelial. Our studies will yield new information on the biochemical mechanisms involved in autacoid mediator synthesis during receptor-mediated endocytosis of immune aggregates, zymosan, endotoxin and/or other particulate materials. We will investigate the regulatory mechanisms involved in the response of the liver parenchyma (hepatocytes) to mediators generated during particulate challenge and to autacoid mediator infusion directly into the hepatic vasculature. Such responses include pronounced glycogenolysis, vasoconstriction, increased then decreased oxygen consumption, etc. We will investigate the mechanism(s) involved in oxygen radical generation following mediator synthesis and/or infusion and pursue means to minimize the potential damaging effects of this apparent oxidative stress reaction in the liver in response to acute trauma. Our studies will include a careful, hopefully innovative analysis of cellular fluxes using compartmental analysis and multiple indicator dilution techniques in the perfused liver and in isolated cell preparations. The involvement of the polyphosphoinositide/inositol polyphosphate/calcium signalling system in both mediator production and mediator mechanism(s) of action will be characterized in the isolated cultured cells. Finally, in a minor study we will continue to pursue our investigations on the regulation of glycine catabolism in the liver. The regulatory mechanisms to be explored in this study likely have little to do with the classical hormonal glucoregulatory signalling systems involved in the day-to-day maintenance of hepatic carbohdyrate metabolism. The proposed research is significant because it will provide new and important information concerning how the liver responds to acute pathophysiological trauma, especially in situations such as acute anaphylaxis or endotoxemia and also in other chronic conditions during which an individual may be overwhelmed with immune complexes of other particulate material which must be cleared by the regiculoendothelial system.