Abstract
In this work, an attempt was made to identify the reasons of impaired long-chain fatty acid utilization that waspreviously described in volume-overloaded rat hearts. The most significant data are the following: (1) The slowing down of long-chain fatty acid oxidation in severely hypertrophied hearts cannot be related to a feedback inhibition of carnitine palmitoyltransferase I from an excessive stimulation of glucose oxidation since, because of decreased tissue levels of L-carnitine, glucose oxidation also declines in volume-overloaded hearts. (2) While, in control hearts, the estimated intracellular concentrations of free carnitine are in the range of the respective Km of mitochondrial CPT I, a kinetic limitation of this enzyme could occur in hypertrophied hearts due to a 40% decrease in free carnitine. (3) However, the impaired palmitate oxidation persists upon the isolation of the mitochondria from these hearts even in presence of saturating concentrations of L-carnitine. In contrast, the rates of the conversion of both palmitoyl-CoA and palmitoylcarnitine into acetyl-CoA are unchanged. (4) The kinetic analyses of palmitoyl-CoA synthase and carnitine palmitoyltransferase I reactions do not reveal any differences between the two mitochondrial populations studied. On the other hand, the conversion of palmitate into palmitoylcarnitine proves to be substrate inhibited already at physiological concentrations of exogenous palmitate. The data presented in this work demonstrate that, during the development of a severe cardiac hypertrophy, a fragilization of the mitochondrial outer membrane may occur. The functional integrity of this membrane seems to be further deteriorated by increasing concentrations of free fatty acids which gives rise to an impaired functional cooperation between palmitoyl-CoA synthase and carnitine palmitoyltransferase I. In intact myocardium, the utilization of the generated in situ palmitoyl-CoA can be further slowed down by decreased intracellular concentrations of free carnitine.
Similar content being viewed by others
References
EL Alaoui-Talibi Z, Landormy S, Loirot A, Moravec J: Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts. Am J Physiol 262: H1068–H1074, 1992
Allard MF, Schönekess BO, Henning SL, English DR, Lopaschuk GD: The contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied heart. Am J Physiol 267: H742–H750, 1994
Schönekess BO, Allard F, Lopaschuk GD: Propionyl-L-carnitine improvement of hypertrophied heart function is accompanied by an increase in carbohydrate oxidation. Circ Res 77: 726–734, 1995
Taegtmayer H, Overturf ML: Effect of moderate hypertension on cardiac function and metabolism in the rabbit. Hypertension 11: 416–426, 1988
Bishop SP, Altschuld RA: Increased glycolytic metabolism in cardiac hypertrophy and congestive heart failure. Am J Physiol 250: 153–159, 1970
Reibel DK, Uboh CE, Kent RL: Altered coenzyme A and carnitine metabolism in pressure-overloaded hypertrophied hearts. Am J Physiol 244: H2090–H2097, 1994
Broderick TL, Quinney HA, Lopaschuk GD: Carnitine stimulation of glucose oxidation in fatty acid perfused isolated working rat heart. J Biol Chem 267(6): 3758–3763, 1992
Saddik M, Gamble J, Wittels LA, Lopaschuk GD: Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 239: 43–49, 1993
Bowé C, Nzonzi J, Corsin A, Moravec J, Feuvray D: Lipid intermediates in chronically volume-overloaded rat hearts. Pflügers Arch 402: 317–320, 1984
Long CS, Haller RG, Foster DW: Kinetics of carnitine dependent fatty acid oxidation: implication of human carnitine deficiency. Neurology 32: 663–666, 1982
Fiol CJ, Kerner J, Bieber LL: Effect of malonyl-CoA on the kinetics and substrate cooperativity of membrane bound carnitine palmitoyltransferase of rat heart mitochondria. Biochim Biophys 916: 462–492, 1987
Schulz H: Beta-oxidation of fatty acids. Biochim Biophys Acta 1081: 109–120, 1991
Wang HY, Baxter CF, Schulz H: Regulation of fatty acid oxidation in rat heart mitochondria. Arch Biochem Biophys 289: 274–280, 1991
Abdel-aleem S, Nada MA, Sayed-Ahmed M, Hendrichson SC, St Louis J, Walthall HP, Lowe JE: Regulation of fatty acid oxidation by acetyl-CoA generated from glucose utilization in isolated myocytes. J Mol Cell Cardiol 28: 825–833, 1996
Reibel DK, O'Rourke B, Foster A, Hutchinson H, Uboh CE, Kent RL: Altered phospholipid metabolism in pressure overloaded hypertrophied hearts. Am J Physiol 250: H1–H6, 1986
Panagia V, Michiel DF, Khatter JC, Dhalla KS, Singal PK, Dhalla NS: Sarcolemmal alterations in cardiac hypertrophy due to pressure overload in pigs. In: FL Abel, WH Newman (eds). Functional Aspects of the Normal, Hypertrophied and Failing Heart. M. Nijhoff, Hague, 1984, pp 268–277
Clouet P, Niot I, Bezard J: Pathway of α-linolenic acid through the mitochondrial outer membrane in the rat liver and influence on the rate of oxidation. Comparison with linoleic and oleic acids. Biochem J 263: 867–873, 1989
Brandes R, Arad R, Bar Tana J: Translocation of long-chain fatty acids into lecithin liposomes containing the long-chain fatty acyl-CoA synthase. FEBS Lett 123(2): 295–299, 1981
Cook GA, Lappi MD: Carnitine palmitoyltransferase in the heart is controlled by a different mechanism than the hepatic enzyme. Mol Cell Biochem 116: 39–45, 1992
Pauly DF, Yoon S, Mc Millin JB: Carnitine acylcarnitine translocase in ischemia; evidence for sulfhydryl groups modifications. Am J Physiol 253: H1557–H1565, 1987
Ben Cheikh R, Guendouz A, Moravec J: Control of oxidative metabolism in volume-overloaded rat hearts; effect of different lipid substrates. Am J Physiol 266: H2090–H2097, 1994
Saddik M, Lopaschuk GD: Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 266: 8162–8170, 1991
Williamson JR, Corkey B: Assays of intermediates of the citric acid cycle and related compounds by fluorimetric methods. In: SP Colowick, NO Kaplan (eds). Methods in Enzymology, Vol 13. Academic Press, New York, 1969, pp 439–513
McGarry JD, Foster DW: An improved and simplified radioisotopic assay for the determination of free and esterified carnitine. J Lipid Res 17: 277–281, 1976
Lindenmayer GE, Sordahl LA, Schwartz A: Evaluation of oxidative phosphorylation in cardiac mitochondria from normal and failing hearts. Circ Res 23: 439–450, 1968
Norseth J, Normann PT, Flatmark T: Hydrodynamic parameters and isolation of mitochondria, microperoxisomes and microsomes of rat hearts. Biochim Biophys Acta 719: 569–579, 1982
Gornall AG, Barawill CJ, David MM: Determination of serum proteins by means of the Biuret reaction. J Biol Chem 177: 751–766, 1949
Murthy MSR, Pande SV: Malonyl-CoA binding site and overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc Natl Acad Sci 84: 378–382, 1987
Sottocasa, GL, Kuylenstierna B, Ernster L, Bergstrand A: An electron transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol 61: 188–200, 1974
Leighton F, Poole B, Lazarow PB, De Duve C: Synthesis and turnover of rat liver peroxisomes. Turnover of peroxisome proteins. J Cell Biol 41: 536–546, 1969
Richard GH, Johnson RN: The steady state concentration of CoA-SH and CoA thioster, citrate and isocitrate during tricarboxylate cycle oxidations in rabbit heart mitochondria. J Biol Chem 250: 8361–8375, 1975
Pauly DF, McMillin JB: Importance of acyl-CoA availability in the interpretation of carnitine palmitoyltransferase activity. J Biol Chem 34: 18160–18167, 1988
Malher HR, Cordes EH: Enzymes kinetics. In: Biological Chemistry. Harper International, New York, 1966, pp 219–277
El Alaoui-Talibi Z, Guendouz A, Moravec M, Moravec J: Control of oxidative metabolism in volume-overloaded rat hearts: Effect of propionyl-L-carnitine. Am J Physiol 272: H1615–H1624, 1997
Oram JF, Bennetch SL, Neely JR: Regulation of fatty acid utilization in isolated perfused rat hearts. J Biol Chem 248: 5299–5309, 1973
McGarry JD, Hills SE, Long CS, Foster DW: Observations on the affinity for carnitine and malonyl-CoA sensitivity of carnitine palmitoyltransferase I in animal and human tissues. Biochem J 214: 21–28, 1983
Gavino GR, Gavino VC: Rat liver outer mitochondrial carnitine palmitoyltransferase activity towards long-chain polyunsaturated fatty acids and their CoA esters. Lipids 26: 266–270, 1991
Lopaschuk GD, Gamble J: Acetyl-CoA carboxylase: an important regulator of fatty acid oxidation in the heart. Can J Physiol Pharmacol 72: 1101–1109, 1994
Woldegiorgis G, Bremer J, Shrago E: Substrate inhibition of carnitine palmitoyltransferase by palmitoyl-CoA and activation by phospholipides and proteins. Biochim Biophys Acta 837: 135–140, 1985
Bremer J: Carnitine. Metabolism and functions. Physiol Rev 63: 1420–1480, 1983
Broderick TL, Christos SC, Wolf BA, DiDomenico D, Shug AL, Paulson DJ: Fatty acid oxidation and cardiac function in the sodium pivalate model of secondary carnitine deficiency. Metabolism 44: 499–505, 1995
Morris GS, Zhou O, Wolf BA, Christos SC, DiDomenico DF, Shug AL, Paulson DJ: Sodium pivalate reduces cardiac carnitine content and increases glucose oxidation without affecting cardiac functional capacity. Life Sci 57: 2237–2244, 1996
Lopaschuk GD, Belke DD, Gamble J, Hoi T, Schonekess BO: Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1213: 263–276, 1994
Van der Vusse GJ: Accumulation of fatty acids and their carnitine derivatives during myocardial ischemia. In: JW de Jong, R Ferrari (eds). The Carnitine System. Kluwer Academic Publishers, Dordrecht, 1995, pp 53–68
Hunneman DH, Schweiekhardt C: Mass fragmentographic determinations of myocardial free fatty acids. J Mol Cell Cardiol 14: 339–351, 1982
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Christian, B., Zainab, E.AT., Mireille, M. et al. Palmitate oxidation by the mitochondria from volume-overloaded rat hearts. Mol Cell Biochem 180, 117–128 (1998). https://doi.org/10.1023/A:1006851325669
Issue Date:
DOI: https://doi.org/10.1023/A:1006851325669