PROSTAGLANDINS AND THE REGULATION OF HEPATIC PHYSIOLOGY

越来越多的证据表明，三尖杉酯碱发挥作用， 调节肝脏代谢。 我们已经证明，E系列 洋地黄素（PGE）抑制葡萄糖刺激的糖原分解， 肝质膜具有PGE特异性受体。 这项建议会 检验肝脏PGE水平受调节的假设 在代谢状态变化的过程中， 调节葡萄糖和脂质代谢的主要肝脏途径。 分离的肝细胞将用作模型系统。 本 该提案扩展了我们的观察，即PGE抑制激素刺激 通过检测PGE对糖原分解的综合调节作用 葡萄糖和脂质代谢。 PGE的作用将在 各种代谢状态，包括从进食和禁食制备的细胞， 动物和在细胞孵育中直接加入激素后。 的 前列腺素效应的特异性将根据以下方面来定义： 前列腺素结构 我们已经证明PGE抑制激素 cAMP依赖性和cAMP非依赖性刺激糖原分解 途径。 前列腺素E拮抗葡萄糖和葡萄糖代谢其他途径的作用 将定义由cAMP和钙调节的脂质代谢。 的作用 将通过与PGE的变化相关来研究肝脏PGE受体的变化。 受体与PGEs的变化对肝脏代谢的影响。 这项建议 还包括旨在确定内源性调节的研究。 通过表征前列腺素的动力学 在分离的肝细胞中的催化剂和生产。 研究将检查 PGE的分解代谢途径和花生四烯酸的命运 代谢条件变化期间的肝细胞，暴露于激素 和药物干预来测试调节 肝脏前列腺素水平和代谢途径的控制。 使用药理和生理干预来改变内源性 水平上，研究将检查内源性甘草素的作用， 调节肝脏生理学。 这些都是重要的研究， 阐明了洋地黄素在正常生理学中的关键作用， 在病理状态下具有临床相关性。 药物干预 有可能改变葡萄糖和脂质代谢 这取决于肝脏中前列腺素的作用。 因此，工作描述 这是一个扩展研究的基础， 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.