This study is aimed at elucidating the regulation of fatty acid oxidation in heart muscle and at establishing the modes by which the interrelated pathways of Beta-oxidation and ketone body degradation affect each other. The knowledge thus gained will be important for a complete understanding of metabolic changes that occur in normal and diseased hearts. We have advanced a hypothesis about the regulation of Beta-oxidation in response to changes in the energy demand of heart muscle. To obtain necessary evidence for this hypothesis we will study the inhibition of long-chain acyl-CoA dehydrogenase by metabolites of Beta-oxidation and determine the concentrations of several coenzymes and fatty acid metabolites in heart mitochondria as a function of the respiratory state. Additionally, the effects of several hormones on fatty acid oxidation in isolated heart cells will be evaluated. Since the rate of fatty acid oxidation is dependent on the supply of fatty acids, their intracelluar transport to mitochondria, possibly by a fatty acid binding protein, will be investigated. An ongoing study of the inhibition of Beta-oxidation in coupled mitochondria by substituted fatty acids, e.g. 3-mercaptopropionic acid, will be continued because this study is expected to yield information about the rate-controlling step(s) in Beta-oxidation and may also provide an understanding of the metabolic consequences of an impaired oxidation of fatty acids. It is planned to explore the intramitochondrial organization of the enzymes of Beta-oxidation. Information relevant to this exploration is expected from an ongoing study of the structure and functional properties of the fatty acid oxidation complex from E. coli. To gain an understanding of the dynamic state of the enzymes of Beta-oxidation in mitochondria we plan to study their biosynthesis and turnover. Although the fatty acids can be partially oxidized by peroxisomes, the physiological significance of this process remains to be established. We plan to study the contribution of microbodies to the oxidation of fatty acids in heart muscle and to evaluate the metabolic importance of this process. Finally, we will be studying how fatty acid oxidation and ketone body degradation affect each other.
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