Skip to main content

The Role of Carnitine in Cell Metabolism

  • Chapter

Part of the Molecular Biology Intelligence Unit book series (MBIU)

Abstract

The sequence of basic detections in carnitine research listed be low represents main events which have led to our present understanding of the function of carnitine in the oxidation of fatty acids. This research had a slow start. Carnitine was isolated from meat extracts at the beginning of the century, but in spite of many studies on its biological effects, (reviewed by Fraenkel and Friedman)1 its function remained a riddle for half a century.

Keywords

  • Fatty Acid Oxidation
  • Liver Mitochondrion
  • Citric Acid Cycle
  • Carnitine Palmitoyltransferase
  • Carnitine Deficiency

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.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4615-6005-0_1
  • Chapter length: 37 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   129.00
Price excludes VAT (USA)
  • ISBN: 978-1-4615-6005-0
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   169.99
Price excludes VAT (USA)
Hardcover Book
USD   249.00
Price excludes VAT (USA)

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Fraenkel G, Friedman S. Carnitine. In: Harris RS, Marian GF, Thimann KV, eds. Vitamins and Hormones. Vol 15. New York: Academic Press, 1957:73–118.

    Google Scholar 

  2. Gulewitsch W, Krimberg R. Zur Kenntnis der Extraktivstoffe der Muskeln. Z Physiol Chem 1905; 45:326–330.

    CAS  Google Scholar 

  3. Tomita M, Sendju Y. über die Oxyaminoverbindungen, welche die Biuretreaktion zeigen. III. Spaltung der m-amino-b-oxybuttersäure in die optisch-aktiven Komponenten. Hoppe-Zeyler’s Z Physiol Chem 1927; 169:263–277.

    CAS  Google Scholar 

  4. Carter HE, Bhattacharrya PK, Weidman KR et al. Chemical studies on vitamin BT isolation and characterization as carnitine. Arch Biochem Biophys 1952; 38:405–416.

    PubMed  CAS  Google Scholar 

  5. Fritz IB. The effects of muscle extracts on the oxidation on palmitic acid by liver slices and homogenates. Acta Physiol Scand 1955; 34:367–385.

    PubMed  CAS  Google Scholar 

  6. Friedman S, Fraenkel G. Reversible enzymatic acetylation of carnitine. Arch Biochem Biophys 1955; 59:491–501.

    PubMed  CAS  Google Scholar 

  7. Lindstedt G, Lindstedt S. On the biosynthesis and degradation of carnitine. Biochem Biophys Res Commun 1961; 6:319–323.

    PubMed  CAS  Google Scholar 

  8. Bremer J. Carnitine precursors in the rat. Biochim Biophys Acta 1962; 57:327–335.

    PubMed  CAS  Google Scholar 

  9. Bremer J. Carnitine in intermediary metabolism. Reversible acetyla tion of carnitine by mitochondria. J Biol Chem 1962; 237:2228–2231.

    PubMed  CAS  Google Scholar 

  10. Bremer J. Carnitine in intermediary metabolism. The metabolism of fatty acid esters of carnitine by mitochondria. J Biol Chem 1962; 237:3628–3632.

    PubMed  CAS  Google Scholar 

  11. Fritz IB, Yue KTN. Long-chain carnitine acyltransferase and the role of acylcarnitine derivatives in the catalytic increase of fatty acid oxidation induced by carnitine. J Lipid Res 1963; 4:279–288.

    PubMed  CAS  Google Scholar 

  12. Marquis NR, Fritz IB. The distribution of carnitine, acetylcarnitine and carnitine acetyltransferase in rat tissues. J Biol Chem 1965; 240: 2193–2196.

    PubMed  CAS  Google Scholar 

  13. Norum KR, Farstad M, Bremer J. The submitochondrial distribution of acid:CoA ligase (AMP) and palmityl-CoA: carnitine palmityl-transferase in rat liver mitochondria. Biochem Biophys Res Commun 1966; 24:797–804.

    CAS  Google Scholar 

  14. Yates DW, Shepherd D, Garland PB. Organization of fatty-acid activation in rat liver mitochondria. Nature 1966; 209:1213–1215.

    PubMed  CAS  Google Scholar 

  15. Solberg HE, Bremer J. Formation of branched chain acylcarnitines in mitochondria. Biochim Biophys Acta 1970; 222:372–380.

    PubMed  CAS  Google Scholar 

  16. Home DW, Tanphaichitr V, Broquist HP. Role of lysine in carnitine biosynthesis in Neurospora crassa. J Biol Chem 1971; 246:4373–4375.

    Google Scholar 

  17. Markwell MAK, McGroarty EJ, Bieber LL et al. The subcellular distribution of carnitine acetyltransferases in mammalian liver and kidney. A new peroxisomal enzyme. J Biol Chem 1973; 248:3426–3432.

    PubMed  CAS  Google Scholar 

  18. DiMauro S, DiMauro PM. Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science 1973; 182:929–931.

    PubMed  CAS  Google Scholar 

  19. Engel AG, Angelini C. Carnitine deficiency of human muscle with associated lipid storage myopathy: a new syndrome. Science 1973; 179:899–902.

    PubMed  CAS  Google Scholar 

  20. Ramsay RR, Tubbs PK. The mechanism of fatty acid uptake by heart mitochondria: an acylcarnitine-carnitine exchange. FEBS Lett 1975; 54:21–25.

    PubMed  CAS  Google Scholar 

  21. Pande SV. A mitochondrial carnitine acylcarnitine translocase system. Proc Natl Acad Sci USA 1975; 72:883–887.

    PubMed  CAS  Google Scholar 

  22. McGarry JD, Leatherman GF, Foster DW. Carnitine palmitoyl-transferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem 1978; 253:4128–4136.

    PubMed  CAS  Google Scholar 

  23. Cook GA, Otto DA, Cornell NW. Differential inhibition of keto-genesis by malonyl-CoA in mitochondria from fed and starved rats. Biochem J 1980; 192:955–958.

    PubMed  CAS  Google Scholar 

  24. Bremer J. The effect of fasting on the activity on liver carnitine pamitoyltransferase and its inhibition by malonyl-CoA. Biochim Biophys Acta 1981; 665:628–631.

    PubMed  CAS  Google Scholar 

  25. Murthy MSR, Pande SV. Malonyl-CoA binding site and the overt carnitine palmitoyltransferase activity reside on the oppsite sides of the outer mitochondrial membrane. Proc Natl Acad Sci USA 1987; 84:378–382.

    PubMed  CAS  Google Scholar 

  26. Jacobs BS, Wanders RJA. Fatty acid oxidation in peroxisomes and mitochondria: The first unequivocal evidence for the involvement of carnitine in shuttling propionyl-CoA from peroxisomes to mitochondria. Biochem Biophys Res Commun 1995; 213:1035–1041.

    Google Scholar 

  27. Cederblad G, Lindstedt S. Metabolism of labeled carnitine in the rat. Arch Biochem Biophys 1976; 175:173–180.

    PubMed  CAS  Google Scholar 

  28. Bremer J. Carnitine, metabolism and functions. Physiol Rev 1984; 63:1420–1480.

    Google Scholar 

  29. Carter AL, Frenkel R. The role of the kidney in the biosynthesis of carnitine in the rat. J Biol Chem 1974; 254:10670–10674.

    Google Scholar 

  30. Erfle JD. Hydroxylation of-butyrobetaine by rat and ovine tissues. Biochem Biophys Res Commun 1975; 64:553–557.

    PubMed  CAS  Google Scholar 

  31. Brooks DE, Mclntosh JEA. Turnover of carnitine in rat tissues. Biochem J 1975; 148:439–445.

    PubMed  CAS  Google Scholar 

  32. Cederblad G, Lindstedt S, Lundholm K. Concentration of carnitine in human muscle tissue. Clin Chim Acta 1974; 53:311–321.

    PubMed  CAS  Google Scholar 

  33. Brooks DE. Carnitine in the male reproductive tract and its relation to the metabolism of the epididymis and spermatozoa. In: Frenkel RA, McGarry JD, Eds. Carnitine Biosynthesis, Metabolism, and Functions. New York: Academic Press 1980:219–2335.

    Google Scholar 

  34. Rebuche CJ, Lehman LJ, Olson AL. e-N-Trimethyllysine availability regulates the rate of carnitine biosynthesis in the growing rat. J Nutr 1986; 116:751–759.

    Google Scholar 

  35. Hokland BM, Bremer J. Metabolism and excretion of carnitine and acylcarnitines in the perfused rat kidney. Biochim Biophys Acta 1986; 886:223–230.

    PubMed  CAS  Google Scholar 

  36. 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.

    PubMed  CAS  Google Scholar 

  37. Engel AG, Rebouch CJ, Wilson DM et al. Primary systemic carnitine deficiency II. Renal handling of carnitine. Neurology 1981; 31: 819–825.

    PubMed  CAS  Google Scholar 

  38. Vary TC, Neely JR. Sodium dependence of carnitine transport in isolated perfused adult rat hearts. Am J Physiol 1983; 244:H247–H252.

    PubMed  CAS  Google Scholar 

  39. Shaw RD, Ulysses B, Hamilton JW et al. Carnitine transport in rat small intestine. Am J Physiol 1983; 245:G376–G381.

    PubMed  CAS  Google Scholar 

  40. Rebouche CJ, Mack DL. Sodium gradient-stimulated transport of L-carnitine into renal brush border membrane vesicles: kinetics, specificity, and regulation by dietary carnitine. Arch Biochem Biophys 1984; 235:393–402.

    PubMed  CAS  Google Scholar 

  41. Siliprandi N, Di Lisa F, Pivetta A et al. Transport and function of L-carnitine and L-propionylcarnitine: relevance to some cardiomyopathies and cardiac ischemia (Review). Z Cardiol 1987; 76 Suppl 5:34–40.

    CAS  Google Scholar 

  42. Rebouche CJ. Effect of dietary carnitine isomers and-butyrobetaine on L-carnitine biosynthesis and metabolism in the rat. J Nutr 1983; 113:1906–1913.

    PubMed  CAS  Google Scholar 

  43. Lispal G, Melegh B, Sandor A. Effect of insulin and glucagon on the uptake of carnitine by perfused rat liver. Biochim Biophys Acta 1987; 929:226–228.

    Google Scholar 

  44. Snoswell AM, Koundajakin PP. Relationship between carnitine and coenzyme A esters in tissues of normal and alloxan-diabetic sheep. Biochem J 1972; 127:133–141.

    PubMed  CAS  Google Scholar 

  45. Kispal G, Melegh B, Alkonyi I et al. Enhanced uptake of carnitine by perfused liver following starvation. Biochim Biophys Acta 1987; 896:96–102.

    PubMed  CAS  Google Scholar 

  46. Hokland BM. Uptake, metabolism and release of carnitine and acylcarnitines in the perfused rat liver. Biochim Biophys Acta 1988; 961:234–241.

    PubMed  CAS  Google Scholar 

  47. Marquis NR, Fritz IB. Effects of testosterone on the distribution of carnitine, acetylcarnitine, and carnitine acetyltransferase in tissues of the reproductive system of the male rat. J Biol Chem 1965; 240:2197–2200.

    PubMed  CAS  Google Scholar 

  48. Indiveri C, Tonazzi A, Palmieri F. Identification and purification of the carnitine carrier from rat liver mitochondria. Biochim Biophys Acta 1990; 1020:81–86.

    PubMed  CAS  Google Scholar 

  49. Noël H, Pande SV. An essential requirement of cardiolipin for mi-tochondrial carnitine acylcarnitine translocase activity. Lipid requirement of carnitine acylcarnitine translocase. Eur J Biochem 1986; 155:99–102.

    PubMed  Google Scholar 

  50. Murthy MSR, Pande SV. Microcompartmentation of transported carnitine, acetylcarnitine and ADP occurs in the mitochondrial matrix. Implications for transport measurements and metabolism. Biochem J 1985; 230:657–663.

    PubMed  CAS  Google Scholar 

  51. Mahadevan S, Sauer F. Carnitine ester hydrolase of rat liver. J Biol Chem 1979; 245:4448–4453.

    Google Scholar 

  52. Mentlein R, Reuter G, Heymann E. Specificity of two different purified acylcarnitine hydrolases from rat liver, their identity with other carboxylesterases, and their possible function. Arch Biochem Biophys 1985; 240:801–810.

    PubMed  CAS  Google Scholar 

  53. Pande SV, Bhuiyan AKMJ, Murthy MSR. Carnitine palmitoyl-transferases: How many and how to distinguish? In: Carter AL, ed. Current Concepts in Carnitine Research. Boca Raton: CRC Press 1992:165–178.

    Google Scholar 

  54. Farrel SO, Fiol CJ, Reddy CK et al. Properties of purified carnitine acyltransferases of mouse liver peroxisomes. J Biol Chem 1984; 259:13089–13095.

    Google Scholar 

  55. Markwell MAK, Tolbert NE, Bieber LL. Comparison of the carnitine acyltransferase activities from rat liver peroxisomes and microsomes. Arch Biochem Biophys 1976; 176:479–488.

    CAS  Google Scholar 

  56. DiDonato CO, Finocchiaro G. Divergent sequences in the 5′ region of cDNA suggest alternative splicing as a mechanism for the generation of carnitine acetyltransferases with different cellular localizations. Biochem J 1994; 303:37–41.

    PubMed  Google Scholar 

  57. Edwards YH, Chase JFA, Edwards MR et al. Carnitine acetyl-transferase: the question of multiple forms. Eur J Biochem 1974; 46:209–215.

    PubMed  CAS  Google Scholar 

  58. Chase JFA, Pearson DJ, Tubbs PK. The preparation of crystalline carnitine acetyltransferase. Biochim Biophys Acta 1965; 96:162–165.

    PubMed  CAS  Google Scholar 

  59. Chase JFA. The substrate specificity of carnitine acetyltransferase. Biochem J 1967; 104:510–518.

    PubMed  CAS  Google Scholar 

  60. Clarke PRH, Bieber LL. Isolation and purification of mitochondrial carnitine octanoyltransferase activities from beef heart. J Biol Chem 1981; 256:9861–9868.

    PubMed  CAS  Google Scholar 

  61. Bremer J, Davis EJ. Flouroacetylcarnitine: metabolism and metabolic effects in mitochondria. Biochim Biophys Acta 1978; 326:262–271.

    Google Scholar 

  62. Chase JFA, Tubbs PK. Conditions for the self-catalyzed inactivation of carnitine acetyltransferase. A novel form of enzyme inhibition. Biochem J 1969; 111:225–235.

    PubMed  CAS  Google Scholar 

  63. Chase JFA, Tubbs PK. Specific alkylation of a histidine residue in carnitine acetyltransferase by bromoacetyl-L-carnitine. Biochem J 1970; 116:713–720.

    PubMed  CAS  Google Scholar 

  64. Brown NF, Anderson RC, Caplan SL et al. Catalytically important domains of rat carnitine palmitoyltransferase II as determined by site-directed mutagenesis and chemical modification. Evidence for a critical histidine residue. J Biol Chem 1994; 269:19157–19162.

    PubMed  CAS  Google Scholar 

  65. Diep QN, Bøhmer T. Increased pivaloylcarnitine in the liver of the sodium pivalate treated rat exposed to clofibrate. Biochim Biophys Acta 1995; 1256:245–247.

    PubMed  Google Scholar 

  66. Ueda M, Tanaka A, Fukui S. Peroxisomal and mitochondrial carnitine acetyltransferases in alkane-grown yeast Candida tropicalis. Eur J Biochem 1981; 124:205–210.

    Google Scholar 

  67. Kahonen MT. Effect of clofibrate treatment on carnitine acyltrans-ferases in different subcellular fractions of rat liver. Biochim Biophys Acta 1976; 428:690–701.

    PubMed  CAS  Google Scholar 

  68. Hovik R, Osmundsen H, Berge R et al. Effects of thia-substituted fatty acids on mitochondrial and peroxisomal ß-oxidation. Studies in vivo and in vitro. Biochem J 1990; 270:167–173.

    PubMed  CAS  Google Scholar 

  69. Leighton F, Bergseth S, Rørtveit T et al. Free acetate produced by rat hepatocytes during peroxisomal fatty acid and dicarboxylic acid oxidation. J Biol Chem 1989; 264:10347–10350.

    PubMed  CAS  Google Scholar 

  70. Skorin C, Nechochea C, Johow V et al. Peroxisomal fatty acid oxidation and inhibitors on the mitochondrial carnitine palmitoyltransferase I in rat isolated hepatocytes. Biochem J 1992; 281:561–567.

    PubMed  CAS  Google Scholar 

  71. Bøhmer T, Bremer J. Propionylcarnitine. Physiological variations in vivo. Biochim Biophys Acta 1968; 152:559–567.

    PubMed  Google Scholar 

  72. Sandor A, Cseko J, Kispal G et al. Surplus acylcarnitines in the plasma of starved rats derive from the liver. J Biol Chem 1990; 265: 22313–22316.

    PubMed  CAS  Google Scholar 

  73. Friolet R, Hoppeler H, Krähenbühl S. Relationship between the co-enzyme A and the carnitine pools in human skeletal muscle at rest and after exhaustive exercise under normic and acutely hypoxic conditions. J Clin Invest 1994; 94:1490–1495.

    PubMed  CAS  Google Scholar 

  74. Brass EP, Fennesey PV, Miller LV. Inhibition of oxidative metabolism by propionic acid and its reversal by carnitine in isolated rat hepatocytes. Biochem J 1986; 236:131–136.

    PubMed  CAS  Google Scholar 

  75. Lysiak W, Toth PP, Suelter CH et al. Quantitation of the efflux of acylcarnitines from rat heart, brain, and liver mitochondria. J Biol Chem 1986; 261:13698–13703.

    PubMed  CAS  Google Scholar 

  76. Holme E, Jacobson C-E, Nordin I et al. Carnitine deficiency induced by pivampicillin and pivmecillinam therapy. Lancet 1989; ii:469–472.

    Google Scholar 

  77. Milkowski AL, Babcock DF, Lardy HA. Activation of bovine epidydimal sperm respiration by caffeine. Its transient nature and relationship to the utilization of acetyl carnitine. Arch Biochem Biophys 1976; 176:250–256.

    PubMed  CAS  Google Scholar 

  78. Kurth L, Fraker P, Bieber L. Utilization of intracellular acylcarnitine pools by mononuclear phagocytes. Biochim Biophys Acta 1994; 1201:321–327.

    PubMed  CAS  Google Scholar 

  79. Childress CC, Sacktor B, Traynor DR. Function of carnitine in the fatty acid oxidase-deficient insect flight muscle. J Biol Chem 1966; 242:754–760.

    Google Scholar 

  80. Barker PJ, Fincham NJ, Hardwick DC. The availability of carnitine acetyltransferase in mitochondria from guinea-pig liver and other tissues. Biochem J 1968; 110:739–746.

    PubMed  CAS  Google Scholar 

  81. Ramsay RR, Derrick JP, Friend AS et al. Purification and properties of the soluble carnitine palmitoyltransferase from bovine liver mitochondria. Biochem J 1987; 244:271–278.

    PubMed  CAS  Google Scholar 

  82. Derrick JP, Ramsay RR. L-Carnitine acyltransferase in intact peroxi-somes is inhibited by malonyl-CoA. Biochem J 1989; 262:801–806.

    PubMed  CAS  Google Scholar 

  83. Lilly K, Bugaisky GE, Umeda PK et al. The medium chain carnitine acyltransferase activity associated with rat liver microsomes is malonyl-CoA sensitive. Arch Biochem Biophys 1990; 280:167–174.

    PubMed  CAS  Google Scholar 

  84. Broadway NM, Saggerson ED. Solubilization and separation of two distinct carnitine acyltransferases from hepatic microsomes: characterization of the malonyl-CoA-sensitive enzyme. Biochem J 1995; 310:985–995.

    Google Scholar 

  85. McMillin JB, Hudson EK, Van Winkle WB. Evidence for malonyl-CoA-sensitive carnitine acyl-CoA transferase in sarcoplasmic reticu-lum of canine heart. J Mol Cell Cardiol 1992; 24:259–268.

    PubMed  CAS  Google Scholar 

  86. Wittels B, Hochstein P. The identification of carnitine palmityl-transferase in erythrocyte membranes. J Biol Chem 1967; 242: 126–130.

    PubMed  CAS  Google Scholar 

  87. Ramsay RR, Mancinelli G, Arduini A. Carnitine palmitoyltransferase in human erythrocyte membrane. Properties and malonyl-CoA sensitivity. Biochem J 1991; 275:685–688.

    PubMed  CAS  Google Scholar 

  88. Murthy MSR, Pande SV. A stress regulated protein, GRP58, a member of thioredoxin superfamily, is a carnitine palmitoyltransferase isoenzyme. Biochem J 1994; 304:31–34.

    PubMed  CAS  Google Scholar 

  89. 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.

    PubMed  CAS  Google Scholar 

  90. Murthy MSR, Pande SV. Some differences in the properties of carnitine palmitoyltransferase activities of the mitochondrial outer and inner membranes. Biochem J 1987; 248:727–733.

    PubMed  CAS  Google Scholar 

  91. Woeltje KF, Kuwajima, M, Foster DW et al. Characterization of the mitochondrial palmitoyltransferase enzyme system. II. Use of detergents and antibodies. J Biol Chem 1987; 262:9822–9827.

    PubMed  CAS  Google Scholar 

  92. Bergseth S, Lund H, Bremer J. Is carnitine palmitoyltransferase inhibited by a malonyl-CoA-binding unit in the mitochondria? Biochem Soc Transactions 1986; 14:671–672.

    CAS  Google Scholar 

  93. Ghadiminejad 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.

    PubMed  CAS  Google Scholar 

  94. Chung CH, Woldegiorgis G, Dai, G et al. Conferral of malonyl Co-enzyme A sensitivity to purified rat heart mitochondrial carnitine palmitoyltransferase. Biochemistry 1992; 31:9777–9783.

    PubMed  CAS  Google Scholar 

  95. Kerner J, Zaluzec E, Gage D et al. Characterization of the malonyl-CoA-sensitive carnitine palmitoyltransferase (CPT0) of a rat heart mitochondrial particle. Evidence that the catalytic unit is CPTi. I Biol Chem 1994; 269:8209–8219.

    CAS  Google Scholar 

  96. Brown NF, Esser V, Foster DW et al. Expression of a cDNA for rat liver carnitine palmitoyltransferase I in yeast establishes that catalytic activity and malonyl-CoA sensitivity reside in a single polypep-tide. J Biol Chem 1994; 269:26438–26442.

    PubMed  CAS  Google Scholar 

  97. Declercq PE, Falck JR, Kuwajima M et al. Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system I. Use of inhibitors. J Biol Chem 1987; 262:9812–9821.

    PubMed  CAS  Google Scholar 

  98. Murthy MSR, Pande SV. Characterization of a solubilized malonyl-CoA-sensitive carnitine palmitoyltransferase from the mitochondrial outer membrane as a protein distinct from the malonyl-CoA-insen-sitive carnitine palmitoyltransferase of the inner membrane. Biochem I 1990; 268:599–604.

    CAS  Google Scholar 

  99. Esser V, Britton CH, Weiss BC et al. Cloning, sequencing, and expression of a cDNA encoding rat liver carnitine palmitoyltransferase I. Direct evidence that a single polypeptide is involved in inhibitor interaction and catalytic function. J Biol Chem 1993; 268:5817–5822.

    PubMed  CAS  Google Scholar 

  100. Kashfi K, Cook GA. Malonyl-CoA inhibits proteolysis of carnitine palmitoyltransferase. Biochem Biophys Res Commun 1991; 178: 600–605.

    PubMed  CAS  Google Scholar 

  101. Esser V, Kuwajima M, Britton CH et al. Inhibitors of mitochondrial carnitine palmitoyltransferase I limit the action of proteases on the enzyme. Isolation and partial amino acid analysis of a truncated form of rat liver isozyme. J Biol Chem 1993; 268:5810–5816.

    PubMed  CAS  Google Scholar 

  102. Kashfi K, Mynatt RL, Cook GA. Hepatic carnitine palmitoyl-transferase-I has two independent inhibitory binding sites for regulation of fatty acid oxidation. Biochim Biophys Acta 1994; 1212: 245–252.

    PubMed  CAS  Google Scholar 

  103. 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.

    PubMed  CAS  Google Scholar 

  104. Solberg HE. Acyl group specificity of mitochondrial pools of carnitine acyltransferases. Biochim Biophys Acta 1974; 360:101–112.

    PubMed  CAS  Google Scholar 

  105. Mynatt RL, Lappi MD, Cook GA. Myocardial carnitine palmitoyltransferase of the mitochondrial outer membrane is not altered by fasting. Biochim Biophys Acta 1992; 1128:105–111.

    PubMed  CAS  Google Scholar 

  106. Christiansen EN, Davis EJ. The effects of coenzyme A and carnitine on steady-state ATP/ADP ratios and the rate of long-chain free fatty acid oxidation in liver mitochondria. Biochim Biophys Acta 1978; 502:17–28.

    PubMed  CAS  Google Scholar 

  107. Singh H, Beckman K, Poulos A. Peroxisomal beta-oxidation of branched chain fatty acids in rat liver. Evidence that carnitine palmitoyltransferase I prevents transport of branched chain fatty acids into mitochondria. J Biol Chem 1994; 269:9514–9520.

    PubMed  CAS  Google Scholar 

  108. Pourfarzam M, Bartlett K. Skeletal muscle mitochondrial ß-oxida-tion of dicarboxylates. Biochim Biophys Acta 1993; 1141:81–89.

    PubMed  CAS  Google Scholar 

  109. Skrede S, Wu P, Osmundsen H. Effects of tetradecylthiopropionic acid and tetradecylthioacrylic acid on rat liver lipid metabolism. Biochem J 1995; 305:591–597.

    PubMed  CAS  Google Scholar 

  110. Clarke RH, Bieber LL. Effect of micelles on the kinetics of purified beef heart mitochondrial carnitine palmitoyltransferase. J Biol Chem 1981; 256:9861–9868.

    PubMed  CAS  Google Scholar 

  111. Bremer J, Norum KR. Palmitoyl-CoA: carnitine O-palmitoyl-transferase in the mitochondrial oxidation of palmitoyl-CoA. Eur J Biochem 1967; 1:427–433.

    PubMed  CAS  Google Scholar 

  112. Bird MI, Saggerson ED. Interacting effects of L-carnitine and malonyl-CoA on rat liver carnitine palmitoyltransferase. Biochem J 1985; 230:161–167.

    PubMed  CAS  Google Scholar 

  113. Bremer J, Norum KR. The mechanism of substrate inhibition of palmitoyl coenzyme A: carnitine acyltransferase in rat liver cells. J Biol Chem 1967; 242:1744–1748.

    PubMed  CAS  Google Scholar 

  114. 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.

    PubMed  CAS  Google Scholar 

  115. Brindle NPJ, Zammit VA, Pogson CI. Regulation of carnitine palmitoyltransferase activity by malonyl-CoA in mitochondria from sheep liver, a tissue with a low capacity for fatty acid synthesis. Biochem J 1985; 232:177–182.

    PubMed  CAS  Google Scholar 

  116. Stephens TW, Cook GA, Harris RA. Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem J 1985; 227:651–660.

    PubMed  CAS  Google Scholar 

  117. Kiorpes TC, Hoerr D, Ho W et al. Identification of 2-tetra-decylglycidyl coenzyme A as the active form of methyl 2-tetra-decylglycidate (methyl palmoxirate) and its characterization as an irreversible, active site-directed inhibitor of carnitine pamitoyl-transferase A in isolated rat liver mitochondria. J Biol Chem 1984; 259:9750–9755.

    PubMed  CAS  Google Scholar 

  118. Brown NF, Weis BC, Husti JE et al. Mitochondrial carnitine palmitoyltransferase I isoform switching in the developing rat heart. J Biol Chem 1995; 270:8952–9857.

    PubMed  CAS  Google Scholar 

  119. 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.

    PubMed  CAS  Google Scholar 

  120. Saggerson ED, Carpenter CA. Carnitine palmitoyltransferase and carnitine octanoyltransferase activities in liver, kidney cortex, adipocyte, lactating mamary gland, skeletal muscle and heart. Relative activities, latency and effect of malonyl-CoA. FEBS Lett 1981; 129:229–232.

    CAS  Google Scholar 

  121. McGarry JD, Mills SE, Long CS et al. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J 1983; 214:21–28.

    PubMed  CAS  Google Scholar 

  122. Singh B, Stakkestad JA, Bremer J et al. Determination of malonyl-Coenzyme A in rat heart, kidney and liver: A comparison between acetyl-coenzyme A and butyryl-coenzyme A as fatty acid synthase primers in the assay procedure. Analytical Biochem 1984; 138: 107–111.

    CAS  Google Scholar 

  123. McGarry JD, Stark MJ, Foster DW. Hepatic malonyl-CoA levels of fed, fasted and diabetic rats as measured using simple radioisotopic assay. J Biol Chem 1978; 253:8291–8293.

    PubMed  CAS  Google Scholar 

  124. Buechler KF, Loewenstein JM. The involvement of carnitine intermediates in peroxisomal fatty acid oxidation: A study with 2-bromofatty acids. Arch Biochem Biophys 1990; 281:233–238.

    PubMed  CAS  Google Scholar 

  125. Murthy MS, Pande SV. Malonyl-CoA-sensitive and-insensitive carnitine palmitoyltransferase activities of microsomes are due to different proteins. J Biol Chem 1994; 269:18283–18286.

    PubMed  CAS  Google Scholar 

  126. Wiggins D, Gibbons GF. The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipopro-tein and its response to hormones and sufphonylureas. Biochem J 1992; 284:457–462.

    PubMed  CAS  Google Scholar 

  127. Broadway NM, Saggerson ED. Microsomal carnitine acyltransferases. Biochem Soc Transactions 1995; 23:490–494.

    CAS  Google Scholar 

  128. Arduini A, Denisova N, Virmani A et al. Evidence for the involvement of carnitine-dependent long-chain acyltransferases in neuronal triglyceride and phospholipid fatty acid turnover. J Neurochem 1994; 62:1530–1538.

    PubMed  CAS  Google Scholar 

  129. Arduini A, Mancinelli G, Radatti GL et al. Role of carnitine and carnitine palmitoyltransferase as integral components of the pathway for membrane phopholipid fatty acid turnover in intact human erythrocytes. J Biol Chem 1992; 267:12673–12681.

    PubMed  CAS  Google Scholar 

  130. Zammit VA, Moir AMB. Monitoring the partitioning of hepatic fatty acids in vivo: keeping track of control. Trends Biochem Sci 1994; 19:313–317.

    PubMed  CAS  Google Scholar 

  131. Moir AMB, Zammit VA. Effects of insulin treatment of diabetic rats on hepatic partitioning of fatty acids between oxidation and esterifi-cation, phospholipid and acylglycerol synthesis, and on the fractional rate of secreting of triacylglycerol in vivo. Biochem J 1994; 304:177–182.

    PubMed  CAS  Google Scholar 

  132. Bøhmer T. Tissue levels of activated fatty acids (acylcarnitines) and the regulation of fatty acid metabolism. Biochim Biophys Acta 1967; 144:259–270

    PubMed  Google Scholar 

  133. Stanley KK, Tubbs PK. The role of intermediates in mitochondrial fatty acid oxidation. Biochem J 1975; 150:77–88.

    PubMed  CAS  Google Scholar 

  134. Bremer J. Pyruvate dehydrogenase, substrate specificity and product inhibition. Eur J Biochem 1969; 8:535–540.

    PubMed  CAS  Google Scholar 

  135. Bremer J. Comparison of acylcarnitines and pyruvate as substrates for rat-liver mitochondria. Biochim Biophys Acta 1966; 116:1–11.

    PubMed  CAS  Google Scholar 

  136. Bremer J, Wojtczak AB. Factors controlling the rate of fatty acid ß-oxidation in rat liver mitochondria. Biochim Biophys Acta 1972; 280:515–530.

    PubMed  CAS  Google Scholar 

  137. Quant PA. Activity and expression of hepatic mitochondrial 3-hy-droxy-3-methylglutaryl-CoA synthase during the starved-to-refed transition. Biochem Soc Trans. 1990; 18:994–995.

    PubMed  CAS  Google Scholar 

  138. McGarry JD, Foster DW. The metabolism of (-)octanoylcarnitine in perfused livers from fed and fasted rats. Evidence for a possible regulatory role of carnitine acyltransferase in the control of ketogenesis. J Biol Chem 1974; 249:7984–7990.

    PubMed  CAS  Google Scholar 

  139. Brass EP, Hoppel CL. Disassociation between acid insoluble acylcarnitines and ketogenesis following carnitine administration in vivo. J Biol Chem 1978; 253:5274–5276.

    PubMed  CAS  Google Scholar 

  140. Parvin R, Pande SV. Enhancement of mitochondrial carnitine and carnitine acylcarnitine translocase-mediated transport of fatty acids into liver mitochondria under ketogenic conditions. J Biol Chem 1979; 254:5423–5429.

    PubMed  CAS  Google Scholar 

  141. Normann PT, Ingebretsen OC, Fiatmark T. On the rate limiting step in the transfer of long-chain acyl groups across the inner membrane of brow adipose tissue mitochondria. Biochim Biophys Acta 1978; 501:286–295.

    PubMed  CAS  Google Scholar 

  142. Saggerson ED, Carpenter CA. Regulation of hepatic carnitine palmitoyltransferase activity during foetal-neonatal transition. FEBS Lett 1982; 150:177–180.

    PubMed  CAS  Google Scholar 

  143. Decaux J-F, Ferre P, Robin D et al. Decreased hepatic fatty acid oxidation at weaning in the rat is not linked to a variation of malonyl-CoA concentration. J Biol Chem 1988; 263:3284–3289.

    PubMed  CAS  Google Scholar 

  144. Borrebaek B. Acylation of carnitine and glycerophosphate in suspensions of rat liver mitochondria at varying levels of palmitate and coenzyme A. Acta Physiol Scand 1975; 95:448–456.

    PubMed  CAS  Google Scholar 

  145. Wong SH, Nestel PJ, Trimble RP et al. The adaptive effects of dietary fish and safflower oil on lipid and lipoprotein metabolism in perfused rat liver. Biochim Biophys Acta 1984; 792:103–109.

    PubMed  CAS  Google Scholar 

  146. Berge RK, Nilsson A, Husøy A-M. Rapid stimulation of liver palmitoyl-CoA synthetase, carnitine palmitoyltransferase and glycerophosphate acyltransferase compared to peroxisomal ß-oxida-tion and palmitoyl-CoA hydrolase in rats fed high-fat diets. Biochim Biophys Acta 1988; 960:417–426.

    PubMed  CAS  Google Scholar 

  147. Clouet P, Niot I, Gresti J et al. Polyunsaturated n-3 and n-6 fatty acids at a low level in the diet alter mitochondrial outer membrane parameters in Wistar rat liver. Nutritional Biochem 1995; 6:626–634.

    CAS  Google Scholar 

  148. Skrede S, Bremer J. Acylcarnitine formation and fatty acid oxidation in hepatocytes from rats treated with tetradecylthioacetic acid (a 3-thia fatty acid). Biochim Biophys Acta 1993; 1167:189–196.

    PubMed  CAS  Google Scholar 

  149. Guzman M, Geelen MJH. Effects of ethanol feeding on the activity and regulation of hepatic carnitine palmitoyltransferase I. Arch Biochem Biophys 1988; 267:580–588.

    PubMed  CAS  Google Scholar 

  150. Cook GA, Gamble MS. Rergulation of carnitine palmitoyltransferase by insulin results in decreased activity and decreased apparent Ki values for malonyl-CoA. J Biol Chem 1987; 262:2050–2055.

    PubMed  CAS  Google Scholar 

  151. Penicaud L, Robin D, Robin P et al. Effect of insulin on the properties of liver carnitine palmitoyltransferase in the starved rat: Assessment by the euglycemic hyperinsulinemic clamp. Metabolism 1991; 40:873–876.

    PubMed  CAS  Google Scholar 

  152. Stakkestad JA, Bremer J. The outer carnitine palmitoyltransferase and regulation of fatty acid metabolism in rat liver in different thyroid states. Biochim Biophys Acta 1983; 750:244–252.

    PubMed  CAS  Google Scholar 

  153. Weinstein I, Cook GA, Heimberg M. Regulation by oestrogen of carnitine palmitoyltranferase in hepatic mitochondria. Biochem J 1986; 237:593–596.

    PubMed  CAS  Google Scholar 

  154. Pegorier J-P, Garcia-Garcia M-V, Prip-Buus C et al. Induction of ketogenesis and fatty acid oxidation by glucagon and cyclic AMP in cultured hepatocytes from rabbit fetuses. Evidence for a decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition after glucagon or cyclic AMP treatment. Biochem J 1989; 264:93–100.

    PubMed  CAS  Google Scholar 

  155. Guzman M, Castro J. Okadaic acid stimulates carnitine palmitoyl-ttransferase I and palmitate oxidation in isolated rat hepatocytes. FEBS Lett 1991; 291:105–108.

    PubMed  CAS  Google Scholar 

  156. Guzman M, Velasco G, Castro J et al. Inhibition of carnitine palmitoyltransferase I by hepatocyte swelling. FEBS Lett 1994; 344:239–241.

    PubMed  CAS  Google Scholar 

  157. Kashfi K, Dory L, Cook GA. Effects of cholesterol loading of mouse macrophages on carnitine palmitoyltransferase activity and sensitivity to inhibition by malonyl-CoA. Biochem Biophys Res Commun. 1991; 177:1121–1126.

    PubMed  CAS  Google Scholar 

  158. Zammit VA. Increased sensitivity of carnitine palmitoyltransferase I activity to malonyl-CoA inhibition after preincubation of intact rat liver mitochondria with micromolar concentrations of malonyl-CoA in vitro. Biochem J 1983; 210:953–956.

    PubMed  CAS  Google Scholar 

  159. Bergseth S, Lund H, Poisson J-P et al. Carnitine palmitoyltransferase: Avtivation and inactivation in liver mitochondria from fed, fasted, hypo-and hyperthyroid rats. Biochem Biophys Acta 1986; 876: 551–558.

    PubMed  CAS  Google Scholar 

  160. Bremer J, Woldegiorgis G, Schalinske K et al. Carnitine palmitoyltransferase. Activation by palmitoyl-CoA and inactivation by malonyl-CoA. Biochim Biophys Acta 1985; 833:9–16.

    PubMed  CAS  Google Scholar 

  161. Ghadiminejad I, Saggerson D. Physiological state and the sensitivity of liver mitochondrial outer membrane carnitine palmitoyltransferase to malonyl-CoA. Correlations with assay temperature, salt concentration and membrane lipid composition. Int J Biochem 1992; 24:1117–1124.

    PubMed  CAS  Google Scholar 

  162. Niot I, Pacot F, Bouchard P et al. Involvement of microsomal vesicles in part of the sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition in mitochondrial fractions of rat liver. Biochem J 1994; 304:577–584.

    PubMed  CAS  Google Scholar 

  163. Stephens TW, Cook GA, Harris RA. Effect of pH on malonyl-CoA inhibition of carnitine palmitoyltransferase I. Biochem J 1983; 212:521–524.

    PubMed  CAS  Google Scholar 

  164. Mynatt RL, Greenhaw JJ, Cook GA. Cholate extracts of mitochondrial outer membranes increase inhibition by malonyl-CoA of carnitine palmitoyltransferase-I by a mechanism involving phospholip-ids. Biochem J 1994; 299:761–767.

    PubMed  CAS  Google Scholar 

  165. Kolodziej MP, Zammit VA. Sensitivity of inhibition of rat liver mitochondrial outer membrane carnitine palmitoyltransferase by malonyl-CoA to chemical-and temperature-induced changes in membrane fluidity. Biochem J 1990; 272:421–425.

    PubMed  CAS  Google Scholar 

  166. Malewiak M-I, Griglio S, Le Liepvre X. Relationship between lipo-genesis, ketogenesis, and malonyl-CoA content in isolated hepato-cytes from the obese Zucker rat adapted to a high-fat diet. Metabolism 1985; 34:604–611.

    PubMed  CAS  Google Scholar 

  167. Mynatt RL, Park EA, Thorngate FE et al. Changes in carnitine palmitoyltransferase-I mRNA abundance produced by hyperthyroidism and hypothyroidism. Parallel changes in activity. Biochim Biophys Res Commun 1994; 201:932–937.

    CAS  Google Scholar 

  168. Thumelin S, Esser V, Charvy D et al. Expression of liver carnitine palmitoyltransferase I and II genes during development in the rat. Biochem J 1994; 300:583–587.

    PubMed  CAS  Google Scholar 

  169. Park EA, Mynatt RL, Cook GA et al. Insulin regulates enzyme activity, malonyl-CoA sensitivity and mRNA abundance of hepatic carnitine palmitoyltranferase I. Biochem J 310:853–858.

    Google Scholar 

  170. Kolodziej MP, Zammit VA. Re-evaluation of the interaction of malonyl-CoA with rat liver mitochondrial carnitine palmitoyltransferase system by using purified outer membranes. Biochem J 1990; 267:85–90.

    PubMed  CAS  Google Scholar 

  171. Cook GA, Cox KA. Hysteretic behaviour of carnitine palmitoyltransferase. The effect of preincubation with malonyl-CoA. Biochem J 1986; 236:917–919.

    PubMed  CAS  Google Scholar 

  172. Harano Y, Kashiwagi A, Kojima H et al. Phosphorylation of carnitine palmitoyltransferase and activation by glucagon in isolated rat hepatocytes. FEBS Lett 1985; 188:267–272.

    PubMed  CAS  Google Scholar 

  173. Guzman M, Kolodziej MP, Caldwell A et al. Evidence against direct involvement of phosphorylation in the activation of carnitine palmitoyltransferase by okadaic acid in rat hepatocytes. Biochem J 1994; 300:693–699.

    PubMed  CAS  Google Scholar 

  174. Bremer J. The carnitine-dependent pathways in heart muscle. In: De Jong JW, Ferrari R, eds. The carnitine system. A new therapeutical approach to cardiovascular diseases. Kluwer Academic Publishers, Dordrecht 1995; 7–20.

    Google Scholar 

  175. Oram JF, Bennetch SL, Neely JR. Regulation of fatty acid utilization in isolated perfused rat hearts. J Biol Chem 1973; 248:5299–5309.

    PubMed  CAS  Google Scholar 

  176. Saddik M, Gamble J, Witters LA et al. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 1993; 268:25836–25845.

    PubMed  CAS  Google Scholar 

  177. Guzman M, Castro J. Effect of endurance excercise on palmitoyltransferase I from rat heart, skeletal muscle and liver mitochondria. Biochim Biophys Acta 1988; 963:562–565.

    PubMed  CAS  Google Scholar 

  178. McMillin JB, Wang D, Witters LA et al. Kinetic properties of carnitine palmitoyltransferase I in cultured neonatal rat cardiac myocytes. Arch Biochem Biophys 1994; 312:375–384.

    PubMed  CAS  Google Scholar 

  179. Kvannes J, Eikhom TS, Flatmark T. The peroxisomal ß-oxidation enzyme system of rat heart. Basal level and effect of the peroxisome proliferator clofibrate. Bichim Biophys Acta 1994; 12ol:203–216.

    Google Scholar 

  180. Crespin SR, Greenough WG, Steinberg D. Stimulation of insulin secretion by long-chain free fatty acids. A direct pancreatic effect. J Clin Invest 1973; 52:1979–1984.

    PubMed  CAS  Google Scholar 

  181. Prentki M, Vischer S, Glennon MC et al. Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 1992; 267:5802–5810.

    PubMed  CAS  Google Scholar 

  182. Malaisse WJ, Best L, Kawazu S et al. Fuel metabolism in islets. Arch Biochem Biophys 1983; 224:102–110.

    PubMed  CAS  Google Scholar 

  183. Shrago E, MacDonald MJ, Woldegiorgis G et al. The role of car-nitine palmitoyltransferase and carnitine in the metabolism of pancreatic islets. In: Borum PR, Ed. Clinical aspects of human carnitine deficiency. New York: Pergamon Press 1986:28–37.

    Google Scholar 

  184. Chen S, Ogawa A, Ohneda M et al. More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic ß-cell signaling. Diabetes 1994; 43:878–883.

    PubMed  CAS  Google Scholar 

Download references

Authors

Rights and permissions

Reprints and Permissions

Copyright information

© 1997 Landes Bioscience

About this chapter

Cite this chapter

Bremer, J. (1997). The Role of Carnitine in Cell Metabolism. In: Carnitine Today. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-6005-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-6005-0_1

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-412-13271-1

  • Online ISBN: 978-1-4615-6005-0

  • eBook Packages: Springer Book Archive