REGULATION OF MYOCARDIAL FATTY ACID METABOLISM

本申请中提出的研究旨在确定 全面控制心肌中的脂肪酸代谢。一个主要部分 的工作涉及到确定控制的机制 脂肪的基本辅因子--辅酶A和肉碱的组织水平 酸代谢。辅酶A合成的速率控制步骤 泛酸将通过测量合成和合成的速度来确定 使用灌流的心脏和心脏的途径的中间产物的组织水平 分离的线粒体。当这些步骤被确定后，这些酶 催化反应将被分离并调节这一活性 将在体外进行测定。肉碱不是由心脏合成的 肌肉。肉碱跨质膜转运的控制将 在灌输的心中坚定。胞质和线粒体的作用 辅酶A和肉碱水平在控制脂肪酸代谢中的作用 将在灌流的心脏中确定，在那里这些组织水平 辅因子是可以改变的。乳酸盐抑制脂肪酸氧化和 这种效应的机制尚不清楚。乳酸盐增加的假说 抑制外线粒体的心肌丙二酰辅酶A水平 肉碱-酰基辅酶A转移酶将在灌流的大鼠心脏中进行研究。

The studies proposed in this application are directed toward detemining the overall control of fatty acid metabolism in cardiac muscle. A major part of the work is concerned with determining the mechanism of control of tissue levels of coenzyme A and carnitine, essential cofactors for fatty acid metabolism. The rate controlling steps for coenzyme A synthesis from pantothenic acid will be determined by measuring rates of synthesis and tissue levels of intermediates in the pathway using the perfused heart and isolated mitochondria. When these steps are identified, the enzymes catalyzing the reactions will be isolated and regulation of this activity will be determined in vitro. Carnitine is not synthesized by cardiac muscle. The control of carnitine transport across the plasma membrane will be determined in perfused hearts. The role of cytosolic and mitochondrial levels of coenzyme A and carnitine in controlling fatty acid metabolism will be determined in perfused hearts where the tissue levels of these cofactors can be altered. Lactate inhibits fatty acid oxidation and the mechanism of this effect is unknown. The hypothesis that lactate increases myocardial levels of malonyl CoA which inhibits the outer mitochondrial carnitine-acyl CoA transferase will be investigated in perfused rat hearts.