PROSTAGLANDINS AND THE REGULATION OF HEPATIC PHYSIOLOGY

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An increasing body of evidence suggests that prostaglandins play a role to modulate hepatic metabolism. We have demonstrated that E-series prostaglandins (PGE) inhibit hormone-stimulated glycogenolysis and that liver plasma membranes have a PGE specific receptor. This proposal will test the hypotheses that hepatic PGE levels are subject to regulation during changes in metabolic state and that variations in these levels modulate the major hepatic pathways of glucose and lipid metabolism. Isolated hepatocytes will be used as the model system. The present proposal extends our observation that PGE inhibits hormone stimulated glycogenolysis by examining the effects of pge on the integrated regulation of glucose and lipid metabolism. The actions of PGE will be studied under various metabolic states, including cells prepared from fed and fasted animals and after direct addition of hormones to cell incubations. The specificity of the prostaglandin effect will be defined with respect to prostaglandin structure. We have demonstrated that PGE inhibits hormone stimulated glycogenolysis by both cAMP-dependent and cAMP-independent pathways. The effects of PGE to antagonize other pathways of glucose and lipid metabolism regulated by cAMP and calcium will be defined. The role of the hepatic PGE receptor will be studied by correlating changes in PGE receptor with changes in PGEs effects on hepatic metabolism. This proposal also includes studies designed to define the regulation of endogenous prostaglandin levels by characterizing the kinetics of prostaglandin catabolism and production in the isolated hepatocyte. Studies will examine the catabolic pathways for PGE and the fate of arachidonic acid in hepatocytes during changes in metabolic conditions, exposure to hormones and pharmacologic interventions to test the relationship between regulation of hepatic prostaglandin levels and control of the metabolic pathways. Using both pharmacologic and physiologic interventions to alter endogenous levels, studies will examine the role of endogenous prostaglandins in the regulation of hepatic physiology. These are important studies in elucidating a critical role for prostaglandins in normal physiology and may have clinical relevance in pathologic states. Pharmacologic intervention in this system has the potential to change glucose and lipid metabolism depending on prostaglandin actions in the liver. Thus the work described here is a basis for expanded studies of the role of prostaglandins in hepatic physiology.