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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL018089-14
Application #
3335543
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1978-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1990-06-30
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost
Name
City College of New York
Department
Type
Schools of Arts and Sciences
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
Abbas, A S; Wu, G; Schulz, H (1998) Carnitine acetyltransferase is not a cytosolic enzyme in rat heart and therefore cannot function in the energy-linked regulation of cardiac fatty acid oxidation. J Mol Cell Cardiol 30:1305-9
Yao, K W; Schulz, H (1996) Intermediate channeling on the trifunctional beta-oxidation complex from pig heart mitochondria. J Biol Chem 271:17816-20
Nada, M A; Abdel-Aleem, S; Schulz, H (1995) On the rate-limiting step in the beta-oxidation of polyunsaturated fatty acids in the heart. Biochim Biophys Acta 1255:244-50
Mao, L F; Chu, C; Luo, M J et al. (1995) Mitochondrial beta-oxidation of 2-methyl fatty acids in rat liver. Arch Biochem Biophys 321:221-8
Luo, M J; Mao, L F; Schulz, H (1995) Short-chain 3-hydroxy-2-methylacyl-CoA dehydrogenase from rat liver: purification and characterization of a novel enzyme of isoleucine metabolism. Arch Biochem Biophys 321:214-20
Yang, S Y; He, X Y; Schulz, H (1995) Glutamate 139 of the large alpha-subunit is the catalytic base in the dehydration of both D- and L-3-hydroxyacyl-coenzyme A but not in the isomerization of delta 3, delta 2-enoyl-coenzyme A catalyzed by the multienzyme complex of fatty acid oxidation from Biochemistry 34:6441-7
Yang, S Y; He, X Y; Styles, J et al. (1994) Primary structure of the large subunit of trifunctional beta-oxidation complex from pig heart mitochondria. Biochem Biophys Res Commun 198:431-7
Yao, K W; Mao, L F; Luo, M J et al. (1994) The relationship between mitochondrial activation and toxicity of some substituted carboxylic acids. Chem Biol Interact 90:225-34
Mao, L F; Chu, C; Schulz, H (1994) Hepatic beta-oxidation of 3-phenylpropionic acid and the stereospecific dehydration of (R)- and (S)-3-hydroxy-3-phenylpropionyl-CoA by different enoyl-CoA hydratases. Biochemistry 33:3320-6
Chu, C; Mao, L F; Schulz, H (1994) Estimation of peroxisomal beta-oxidation in rat heart by a direct assay of acyl-CoA oxidase. Biochem J 302 ( Pt 1):23-9

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