STRUCTURAL SPECIFICITY FOR PROSTAGLANDIN EFFECTS ON HEPATOCYTE GLYCOGENOLYSIS

Prostaglandins (PGs) are known to have effects on hepatic glucose metabolism. Some actions of PGs in intact liver systems may not involve PG effects directly at the level of the hepatocyte. To define the ability of structurally distinct prostaglandins to affect hepatocyte metabolism directly, the regulation of glycogenolysis was studied in hepatocytes isolated from male Sprague-Dawley rats. PGF(2α) and PGB2 inhibited glucagon-stimulated glycogenolysis in the hepatocyte system. Pinane thromboxane A2 (PTA2) and PGD2 had no effect on glucagon-stimulated glycogenolysis. Consistent with their inhibition of glucagon-stimulated glycogenolysis, PGB2 and PGF(2α) inhibited glucagon-stimulated hepatocyte cyclic AMP accumulation. These actions of PGB2 and PGF(2α) are identical with those previously reported for PGE2. Additionally, PGE2, PGF(2α) and PGB2 inhibited glucagon-stimulated adenylate cyclase activity in purified hepatic plasma membranes. In contrast, PGF(2α), PGD2 and PTA2 were all without effect on basal rates of hepatocyte glycogenolysis or hepatocyte cyclic AMP content. PGE2 also inhibited glycogenolysis stimulated by the α-adrenergic agonist phenylephrine. Exogenous arachidonic acid was not able to reproduce the effects of PGE2 or PGF(2α) on hepatocyte glycogenolysis, consistent with an extra-hepatocyte source of the prostaglandins in the intact liver. Thus PGE2 and PGF(2α) act specifically to inhibit glucagon-stimulated adenylate cyclase activity. No prostaglandin tested was found to stimulate glycogenolysis. PGE2 and PGF(2α) may represent intra-hepatic modulators of hepatocyte glucose metabolism.