REGULATION OF MYOCARDIAL FATTY ACID METABOLISM

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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.