Abstract
The behavior of a computer model of metabolism in glucose- and palmitate-perfused rat hearts was interpreted by sensitivity analysis to explain why the heart preferentially utilizes fatty acids as fuel even in the presence of substantial exogenous glucose. The sensitivity functions identified those metabolites and enzymes which were most important in regulating the metabolic rate and determined which enzymes set the levels of the critical metabolites. Control of the mitochondrial redox potential and the distribution of coenzyme A thioesters regulated the rate of fatty acid utilization while strong inhibition of citrate synthetase resulted in accumulation of acetyl CoA and supprersion of pyruvate oxidation. Glycolysis was limited by the cytosolic ATP/ADP ratio set largely by the creatine shuttle. Metabolic control appears to be widely distributed rather than localized at “key” enzymes. Metabolite levels are usually set by enzymes controlled by modifiers whereas metabolic flux is regulated by the enzymes that produce ligands for the modifier-controlled enzymes.
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References
Bremer, J. Factors influencing carnitine-dependent oxidation of fatty acids. In:Cellular Compartmentation and Control of Fatty Acid Metabolism, edited by F.C. Gran. New York: Academic Press, 1968, pp. 65–88.
Bremer, J. and E.J. Davis. Phosphorylation coupled to acyl-coenzyme A dehydrogenase-linked oxidation of fatty acids by liver and heart mitochondria.Biochim. Biophys. Acta 275:298–301, 1972.
Frank, P.M.Introduction to System Sensitivity Theory, New York: Academic, 1978, pp. 28–32.
Fong, J.C. and H. Schulz. On the rate-determining step of fatty acid oxidation by 4-pentenoic acid.J. Biol. Chem. 253:6917–6922, 1978.
Heinrich, R. and T.A. Rapoport. Mathematical analysis of multienzyme systems: Steady state and transient control.BioSystems 7:130–136, 1975.
Kacser, H. and J.A. Burns. Molecular democracy: who shares the control?Biochem. Soc. Trans. 7: 1149–1160, 1979.
Kohn, M.C., M.J. Achs, and D. Garfinkel. Computer simulation of metabolism in pyruvate-perfused rat heart. II. Krebs cycle.Am. J. Physiol. 237:R159-R166, 1979.
Kohn, M.C. and E. Chiang. Metabolic network sensitivity analysis.J. Theor. Biol. 98:109–126, (1982).
Kohn, M.C. and D. Garfinkel. Computer simulation of metabolism in palmitate-perfused rat heart. I. Palmitate oxidation.Ann. Biomed. Eng. 11:361–384, 1983.
Kohn, M.C. and D. Garfinkel. Computer simulation of metabolism in palmitate-perfused rat heart. II. Behavior of complete model.Ann. Biomed. Eng. 11:511–531, 1983.
McMinn, C.L. and J.H. Ottaway. On the control of enzyme pathways.J. Theor. Biol. 56:57–73, 1976.
Neely, J.R., M.J. Rovetto, and J.F. Oram. Myocardial utilization of carbohydrate and lipids.Prog. Cardiovasc. Dis. 15:259–329, 1972.
Normann, P.T. and T. Flatmark. Long-chain acyl-CoA synthetase and ‘outer’ long-chain acyltransferase of intact brown adipose tissue mitochondria.Biochim. Biophys. Acta 530:461–473, 1978.
Opie, L.H. Role of carnitine in fatty acid metabolism of normal and ischemic myocardium.Am. Heart J. 97:375–388, 1979.
Oram, J.F., S.L. Bennetch, and J.F. Neely. Regulation of fatty acid utilization in isolated perfused rat hearts.J. Biol. Chem. 248:5299–5309, 1973.
Oram, J.F., J. Idell-Wenger and J.R. Neely. Regulation of long chain fatty acid activation in heart muscle.J. Biol. Chem. 250:73–78, 1975.
Ottaway, J.H. and C.L. McMinn. Control points in the citric acid cycle. In:Enzyme Regulation and Mechanism of Action, edited by P. Mildner and B. Ries. New York: Pergamon Press, 1980, pp.69–82.
Pande, S.V. On rate-controlling factors of long chain fatty acid oxidation.J. Biol. Chem. 246:5381–5390, 1971.
Saks, V.A. Creatine kinase isozymes and the control of cardiac contraction. In:Heart Creatine Kinase, edited by W.E. Jacobus and J.S. Ingwall. Baltimore: Williams and Wilkins, 1980, pp. 109–124.
Whitmer, J.T., J.A. Idell-Wenger, M.J. Rovetto, and J.R. Neely. Control of fatty acid metabolism in ischemic and hypoxic hearts.J. Biol. Chem. 253:4305–4309, 1978.
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Kohn, M.C. Computer simulation of metabolism in palmitate-perfused rat heart. III. Sensitivity analysis. Ann Biomed Eng 11, 533–549 (1983). https://doi.org/10.1007/BF02364083
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DOI: https://doi.org/10.1007/BF02364083