PROSTAGLANDINS AND THE REGULATION OF HEPATIC PHYSIOLOGY

越来越多的证据表明，前列腺素在 调节肝脏代谢。我们已经演示了E系列 前列腺素(PGE)抑制激素刺激的糖原分解 肝脏质膜上有一种PGE特异性受体。这项提议将 检验肝脏前列腺素E水平受调控的假说 在代谢状态的变化和这些水平的变化期间 调节肝脏糖和脂代谢的主要途径。 将以分离的肝细胞作为模型系统。现在 该提案扩大了我们对前列腺素E抑制激素刺激的观察 前列腺素E对糖原分解的综合调节作用 葡萄糖和脂类新陈代谢。PGE的作用将在以下条件下研究 各种代谢状态，包括从喂养和禁食中制备的细胞 动物和在细胞孵育中直接添加激素后。这个 前列腺素效应的特异性将根据以下方面进行定义 前列腺素结构。我们已经证明前列腺素E抑制荷尔蒙 CAMP依赖和非cAMP依赖刺激糖原分解 小路。前列腺素E拮抗其他途径的葡萄糖和 将定义由cAMP和钙调节的脂代谢。角色 将通过PGE的相关变化来研究肝脏PGE受体的变化 PGEs变化的受体对肝脏代谢的影响。这项建议 还包括旨在定义内源性的调节的研究 前列腺素动力学特征及其对前列腺素水平的影响 分离的肝细胞中的分解代谢和产物。研究将检查 前列腺素E的分解代谢途径和花生四烯酸在体内的去向 肝细胞在代谢条件变化期间，暴露于激素 和药物干预，以测试调节之间的关系 肝脏前列腺素水平和代谢途径的控制。 同时使用药物和生理干预改变内源性 水平，研究将检查内源性前列腺素在 肝生理调节。这些都是关于 阐明前列腺素在正常生理中的关键作用 与病理状态有临床相关性。药物干预 在这个系统中有可能改变葡萄糖和脂肪的代谢 取决于前列腺素在肝脏中的作用。因此，所描述的工作 这是扩大前列腺素作用研究的基础。 肝脏生理学。

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.