Carnitine-dependent pathways in heart muscle

Dedicated to the memory of E. Jack Davis (1930–1993)
  • Jon Bremer
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 162)

Abstract

Heart and skeletal muscle normally cover most of their energy needs by oxidizing fatty acids. When rat heart is offered both glucose and high concentrations of fatty acids, fatty acids are the preferred substrate even in the presence of insulin. Under such conditions 90% of the CO2 produced will derive from fatty acids [1, 2].

Keywords

Fatty Acid Oxidation Erucic Acid Citric Acid Cycle Heart Mitochondrion Carnitine Palmitoyltransferase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Evans JR, Opie LH, Shipp JC. Metabolism of palmitic acid in perfused rat heart. Am J Physiol 1963; 205: 706–707.Google Scholar
  2. 2.
    Saddik M, Lopaschuk GD. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991; 266: 8162–8170.PubMedGoogle Scholar
  3. 3.
    De Jong JW, Hülsmann WC. A comparative study of palmitoyl-CoA synthetase activity in rat-liver, heart and gut mitochondrial and microsomal preparations. Biochim Biophys Acta 1969; 197: 127–135.Google Scholar
  4. 4.
    Webster Jr LT, Gerowin LD, Rakita L. Purification and characteristics of a butyryl-CoA synthetase from bovine heart mitochondria. J Biol Chem 1964; 240: 29–33.Google Scholar
  5. 5.
    Mahler HR, Wakil SJ, Bock RM. Studies on fatty acid oxidation. I. Enzymatic activation of fatty acids. J Biol Chem 1953; 204: 453–467.PubMedGoogle Scholar
  6. 6.
    Bressler R, Witteis B. The effect of diphtheria toxin on carnitine metabolism in the heart. Biochim Biophys Acta 1965; 104: 39–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Mølstad P, Bøhmer T. The effect of diphtheria toxin on the cellular uptake and efflux of L-carnitine. Evidence for a protective effect of prednisolon. Biochim Biophys Acta 1981; 641: 71–78.PubMedCrossRefGoogle Scholar
  8. 8.
    Engel AG, Angelini C. Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: a new syndrome. Science 1973; 179: 899–902.PubMedCrossRefGoogle Scholar
  9. 9.
    Miyazawa S, Ozasa H, Furuta S, Osumi T, Hashimoto T. Purification and properties of carnitine acetyltransferase from rat liver. J Biochem 1983; 93: 439–451.PubMedGoogle Scholar
  10. 10.
    Farrell SO, Bieber LL. Carnitine octanoyltransferase of mouse liver peroxisomes: properties and effect of hypolipidemic drugs. Arch Biochem Biophys 1983; 222: 123–132.PubMedCrossRefGoogle Scholar
  11. 11.
    Maxwell MAK, Tolbert NE, Bieber LL. Comparison of the carnitine acyltransferase activities from rat liver peroxisomes and microsomes. Arch Biochem Biophys 1976; 176: 479–488.CrossRefGoogle Scholar
  12. 12.
    Murthy MSR, Pande SV. Malonyl-CoA binding site and the overt carnitine palmitoyl-transferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc Natl Acad Sci USA 1987; 84: 378–382.PubMedCrossRefGoogle Scholar
  13. 13.
    Norum KR, Bremer J. The localization of acyl coenzyme A: carnitine acyltransferase in rat liver cells. J Biol Chem 1967; 242: 407–411.PubMedGoogle Scholar
  14. 14.
    Clarke RH, Bieber LL. Effect of micelles on the kinetics of purified beef heart mitochondrial carnitine palmitoyltransferase. J Biol Chem 1981; 256: 9861–9868.PubMedGoogle Scholar
  15. 15.
    Solberg HE. Acyl group specificity of mitochondrial pools of carnitine acyltransferases. Biochim Biophys Acta 1974; 360: 101–112.PubMedCrossRefGoogle Scholar
  16. 16.
    Woeltje KF, Esser V, Weis BC et al. Inter-tissue and inter-species characteristics of the mitochondrial carnitine palmitoyltransferase enzyme system. J Biol Chem 1990; 265: 10714–10719.PubMedGoogle Scholar
  17. 17.
    Bremer J, Norum KR. The mechanism of substrate inhibition of palmityl coenzyme A: carnitine acyltransferase in rat liver cells. J Biol Chem 1967; 242: 1744–1748.PubMedGoogle Scholar
  18. 18.
    Derrick JP, Ramsay RR. L-Carnitine acyltransferase in intact peroxisomes is inhibited by malonyl-CoA. Biochem J 1989; 262: 801–806.PubMedGoogle Scholar
  19. 19.
    Skorin C, Nechochea, C, Johow V, Soto U, Grau AM, Bremer J, Leighton F. Peroxisomal fatty acid oxidation and inhibitors on the mitochondrial carnitine palmitoyltransferase I in rat isolated hepatocytes. Biochem J 1992; 281: 561–567.PubMedGoogle Scholar
  20. 20.
    Lund H. Carnitine palmitoyltransferase: characterization of a labile detergent-extracted malonyl-CoA-sensitive enzyme from rat liver mitochondria. Biochim Biophys Acta 1987; 918: 67–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Brosnan JT, Fritz IB. The oxidation of fatty-acyl derivatives by mitochondria from bovine fetal and calf hearts. Can J Biochem 1971; 49: 1296–1300.PubMedGoogle Scholar
  22. 22.
    Warshaw JB, Terry ML. Cellular energy metabolism during fetal development. II. Fatty acid oxidation by the developing heart. J Cell Biol 1970; 44: 354–360.PubMedCrossRefGoogle Scholar
  23. 23.
    Bergseth S, Lund H, Bremer J. Is carnitine palmitoyltransferase inhibited by a malonyl-CoA binding unit in the mitochondria? Biochem Soc Trans 1986; 14: 671–672.PubMedGoogle Scholar
  24. 24.
    Ghaddiminejad I, Saggerson ED. Carnitine palmitoyltransferase (CPT2) from liver mitochondrial inner membrane becomes inhibitable by malonyl-CoA if reconstituted with outer membrane malonyl-CoA binding protein. FEBS Lett 1990; 269: 406–408.CrossRefGoogle Scholar
  25. 25.
    Chung CH, Woldegiorgis G, Dai G, Shrago E, Bieber LL. Conferral of malonyl coenzyme A sensitivity to purified rat heart mitochondrial carnitine palmitoyltransferase. Biochemistry 1992; 31: 9777–9783.PubMedCrossRefGoogle Scholar
  26. 26.
    Kerner J, Bieber, L. Isolation of a malonyl-CoA sensitive CPT/β-oxidation enzyme complex from heart mitochondria. Biochemistry 1990; 29: 4326–4334.PubMedCrossRefGoogle Scholar
  27. 27.
    Zierz S, Engel AG. Different sites of inhibition of carnitine palmitoyltransferase by malonyl-CoA, and by acetyl-CoA and CoA, in human skeletal muscle. Biochem J 1987; 245: 205–209.PubMedGoogle Scholar
  28. 28.
    Esser V, Britton CH, Weis BC, Foster DW, McGarry JD. Cloning, sequencing, and expression of a cDNA encoding rat liver carnitine palmitoyltransferase I. Direct evidence that single polypeptide is involved in inhibitor interaction and catalytic function. J Biol Chem 1993; 268: 5817–5822.PubMedGoogle Scholar
  29. 29.
    Kolodziej MP, Crilly PJ, Corstophine CG, Zammit VA. Development and characterization of a polyclonal antibody against rat liver mitochondrial overt carnitine palmitoyltranferase (CPT I). Distinction of CPT I from CPT II and of isoformes of CPT I in different tissues. Biochem J 1992; 282: 415–421.PubMedGoogle Scholar
  30. 30.
    Saggerson ED, Carpenter CA. Carnitine palmitoyltransferase and carnitine octanoyl-transferase activities in liver, kidney cortex, adipocyte, lactating mammary gland, skeletal muscle and heart. Relative activities, latency and effect of malonyl-CoA. FEBS Lett 1981; 129: 229–232.PubMedCrossRefGoogle Scholar
  31. 31.
    Mills SE, Foster DW, McGarry JD. Interaction of malonyl-CoA and related compounds with mitochondria from different rat tissues. Relationship between ligand binding and inhibition of carnitine palmitoyltransferase I. Biochem J 1983; 214: 83–91.PubMedGoogle Scholar
  32. 32.
    Cook GA, Otto DA, Cornell NW. Differential inhibition of ketogenesis by malonyl-CoA in mitochondria from fed and starved rats. Biochem J 1980; 192: 955–958.PubMedGoogle Scholar
  33. 33.
    Bremer J. The effect of fasting on the activity of liver carnitine palmityltransferase and its inhibition by malonyl-CoA. Biochim Biophys Acta 1981; 665: 628–631.PubMedCrossRefGoogle Scholar
  34. 34.
    Idell-Wenger JA, Grotyohann LW, Neely JR. Coenzyme A and carnitine distribution in normal and ischemic hearts. J Biol Chem 1978; 253: 4310–4318.PubMedGoogle Scholar
  35. 35.
    Pande SV, Parvin R. Characterization of carnitine acylcarnitine translocase system of heart mitochondria. J Biol Chem 1976; 251: 6683–6691.PubMedGoogle Scholar
  36. 36.
    Davis EJ, Bremer J. Studies with isolated surviving rat hearts. Interdependence of free amino acids and citric acid cycle intermediates in muscle. Eur J Biochem 1973; 38: 86–97.PubMedCrossRefGoogle Scholar
  37. 37.
    Bremer J, Davis EJ. Fluoroacetylcarnitine: metabolism and metabolic effects in mitochondria. Biochim Biophys Acta 1973; 326: 262–271.PubMedCrossRefGoogle Scholar
  38. 38.
    Wang H-Y, Baxter CF, Schulz H. Regulation of fatty acid β-oxidation in rat heart mitochondria. Arch Biochem Biophys 1991; 289: 274–280.PubMedCrossRefGoogle Scholar
  39. 39.
    Brooks DE, Mclntosh JEA. Turnover of carnitine by rat tissues. Biochem J 1975; 49: 1296–1300.Google Scholar
  40. 40.
    Hiatt WR, Regensteiner JG, Wolfel EE, Ruff L, Brass EP. Carnitine and acylcarnitine metabolism during exercise in humans. Dependence on skeletal muscle metabolic state. J Clin Invest 1989; 84: 1167–1173.PubMedCrossRefGoogle Scholar
  41. 41.
    Bowman RH. Effect of diabetes, fatty acids, and ketone bodies on tricarboxylic acid cycle metabolism in the perfused rat heart. J Biol Chem 1965; 240: 2308–2321.Google Scholar
  42. 42.
    Lee S-H, Davis EJ. Carboxylation and decarboxylation reactions. Anaplerotic flux and removal of citrate cycle intermediates in skeletal muscle. J Biol Chem 1979; 254: 420–430.PubMedGoogle Scholar
  43. 43.
    Davis EJ, Spydevold Ø, Bremer J. Pyruvate carboxylase and propionyl-CoA carboxylase as anaplerotic enzymes in skeletal muscle mitochondria. Eur J Biochem 1980; 110: 255–262.PubMedCrossRefGoogle Scholar
  44. 44.
    Hülsmann WC, Schneijdenberg CTWM, Verkleij AJ. Accumulation and excretion of long-chain acylcarnitine by rat hearts; studies with aminocarnitine. Biochim Biophys Acta 1991; 1097: 263–269.PubMedCrossRefGoogle Scholar
  45. 45.
    Bremer J. Pyruvate dehydrogenase, substrate specificity and product inhibition. Eur J Biochem 1969; 8: 535–540.PubMedCrossRefGoogle Scholar
  46. 46.
    Lumeng L, Bremer J, Davis EJ. Suppression of the mitochondrial oxidation of (-)-palmityl-carnitine by the malate-aspartate and α-glycerophosphate shuttles. J Biol Chem 1976; 251: 277–284.PubMedGoogle Scholar
  47. 47.
    Bremer J, Wojtczak AB. Factors controlling the rate of fatty acid ßp-oxidation in rat liver mitochondria. Biochim Biophys Acta 1972; 280: 515–530.PubMedCrossRefGoogle Scholar
  48. 48.
    Bremer J, Davis EJ, Borrebæk B. Factors influencing the carnitine-dependent oxidation of fatty acids in the heart. In: Ferrari R, Katz AM, Shug A, Visioli O, editors. Myocardial ischemia and lipid metabolism. New York: Plenum Press, 1984: 15–26.CrossRefGoogle Scholar
  49. 49.
    Oram JF, Bennetch SL, Neely JR. Regulation of fatty acid utilization in isolated perfused rat hearts. J Biol Chem 1973; 248: 5299–5309.PubMedGoogle Scholar
  50. 50.
    Latipää PM. Energy-linked regulation of mitochondrial fatty acid oxidation in the isolated perfused rat heart. J Mol Cell Cardiol 1989; 21: 765–771.PubMedCrossRefGoogle Scholar
  51. 51.
    Singh B, Stakkestad JA, Bremer J, Borrebaek B. Determination of malonyl-CoA in rat heart, kidney and liver: A comparison between acetyl-CoA and butyryl-CoA as fatty acid synthase primers in the assay procedure. Anal Biochem 1984; 138: 107–111.PubMedCrossRefGoogle Scholar
  52. 52.
    Rändle PJ, Garland PB, Hales CN, Newsholm EA, Denton RM, Pogson CI. Interaction of metabolism and the physiological role of insulin. Recent Progr Hormone Res 1966; 22: 1–44.PubMedGoogle Scholar
  53. 53.
    Abdellatif AM, Vies RO. Pathological effects of dietary rapeseed oil in rats. Nutr Metabol 1970; 12: 285–295.CrossRefGoogle Scholar
  54. 54.
    Beare-Rogers JL, Nera EA, Heggtveit HA. Cardiac lipid changes in rats fed oils containing long-chain fatty acids. Can Inst Food Technol J 1971; 4: 120–124.Google Scholar
  55. 55.
    Pinson A, Padieu P. Erucic acid oxidation by beating heart cells in culture. FEBS Lett 1974; 39: 88–90.PubMedCrossRefGoogle Scholar
  56. 56.
    Christophersen BO, Bremer J. Erucic acid — an inhibitor of fatty acid oxidation in rat liver mitochondria. Biochim Biophys Acta 1972; 280: 506–514.PubMedCrossRefGoogle Scholar
  57. 57.
    Heijkenskjöld L, Ernster L. Studies on the mode of action of erucic acid on heart metabolism. Acta Medica Scand 1975; Suppl 585: 75–86.Google Scholar
  58. 58.
    Norseth J. The effect of feeding rats with partially hydrogenated marine oil or rapeseed oil on the chain shortening of erucic acid in perfused heart. Biochim Biophys Acta 1979; 575: 1–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Christiansen RZ, Christiansen EN, Bremer J. The stimulation of erucate metabolism in isolated rat hepatocytes by rape seed oil and hydrogenated marine oil-containing diets. Biochim Biophys Acta 1979; 573: 417–429.PubMedCrossRefGoogle Scholar
  60. 60.
    Buechler KF, Lowenstein JM. The involvement of carnitine intermediates in peroxisomal fatty acid oxidation: a study with 2-bromofatty acids. Arch Biochem Biophys 1990; 281: 233–238.PubMedCrossRefGoogle Scholar
  61. 61.
    Katoh H, Kawakima Y, Watanuki H, Kozyka H, Isono, H. Effects of clofibric acid and tiadenol on cytosolic long-chain acyl-CoA hydrolase and peroxisomal β-oxidation in liver and extrahepatic tissues of rats. Biochim Biophys Acta 1987; 920: 171–179.PubMedCrossRefGoogle Scholar
  62. 62.
    Leighton F, Bergseth S, Rørtveit T, Christiansen EN, Bremer J. Free acetate produced by rat hepatocytes during peroxisomal fatty acid and dicarboxylic acid oxidation. J Biol Chem 1989; 264: 10347–10350.PubMedGoogle Scholar
  63. 63.
    Hokland BM, Bremer J. Formation and excretion of branched-chain acylcarnitines and branched-chain hydroxy acids in the perfused rat kidney. Biochim Biophys Acta 1988; 961: 30–37.PubMedCrossRefGoogle Scholar
  64. 64.
    Hokland BM. Uptake, metabolism and release of carnitine and acylcarnitines in the perfused rat liver. Biochim Biophys Acta 1988; 961: 234–241.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1995

Authors and Affiliations

  • Jon Bremer
    • 1
  1. 1.Institute of Medical BiochemistryUniversity of OsloBlindern, OsloNorway

Personalised recommendations