Current progress from this laboratory has indicated that endotoxin administration affects hepatic glucose metabolism by two different mechanisms: one by acting through the membrane lipid microenvironment and the other by acting on enzyme and receptor proteins. The primary aims of this proposal are to study the causative factors responsible for the endotoxin-induced alterations in membrane lipid profile as well as in enzyme and receptor dynamics as related to the control of hepatic glucose metabolism, and ultimately, to propose a rational remedy for the better management of endotoxic shock. Specifically, we will (i) investigate the kinetic properties of phospholipases A and the responsiveness of these enzymes to various inhibitors, and elucidate mechanisms responsible for the endotoxin-induced activation of phospholipases A; (ii) study alterations of key enzymes responsible for the biosynthesis of membrane phospholipids during endotoxic shock; (iii) investigate the endotoxin-induced changes in the properties and the kinetic characteristics of phospholipid exchange proteins; (iv) study changes in the chemical structure and physical properties of membrane lipids, identify factors which may be responsible for these changes, and assess their association with altered hepatic glucose metabolism during endotoxic shock. Once these tasks are accomplished, our ultimate goal is to prevent the onset, to delay the progression, or to reverse the endotoxin-induced glucose dyshomeostasis and other cellular dysfunction by means of metabolic and/or pharmacologic interventions. These will include the use of liposomes loaded with phospholipase A inhibitors, with lipid stabilizing agents, with adenylate cyclase activators, with adrenergic blockers, with certain metabolites acting as regulators of hepatic glucose metabolism, or with the combination of these agents.
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