Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1987 Dec;80(6):1778–1783. doi: 10.1172/JCI113271

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

R J Wanders 1, C W van Roermund 1, M J van Wijland 1, R B Schutgens 1, J Heikoop 1, H van den Bosch 1, A W Schram 1, J M Tager 1
PMCID: PMC442453  PMID: 3680527

Abstract

The peroxisomal oxidation of the long chain fatty acid palmitate (C16:0) and the very long chain fatty acids lignocerate (C24:0) and cerotate (C26:0) was studied in freshly prepared homogenates of cultured skin fibroblasts from control individuals and patients with peroxisomal disorders. The peroxisomal oxidation of the fatty acids is almost completely dependent on the addition of ATP, coenzyme A (CoA), Mg2+ and NAD+. However, the dependency of the oxidation of palmitate on the concentration of the cofactors differs markedly from that of the oxidation of lignocerate and cerotate. The peroxisomal oxidation of all three fatty acid substrates is markedly deficient in fibroblasts from patients with the Zellweger syndrome, the neonatal form of adrenoleukodystrophy and the infantile form of Refsum disease, in accordance with the deficiency of peroxisomes in these patients. In fibroblasts from patients with X-linked adrenoleukodystrophy the peroxisomal oxidation of lignocerate and cerotate is impaired, but not that of palmitate. Competition experiments indicate that in fibroblasts, as in rat liver, distinct enzyme systems are responsible for the oxidation of palmitate on the one hand and lignocerate and cerotate on the other hand. Fractionation studies indicate that in rat liver activation of cerotate and lignocerate to cerotoyl-CoA and lignoceroyl-CoA, respectively, occurs in two subcellular fractions, the endoplasmic reticulum and the peroxisomes but not in the mitochondria. In homogenates of fibroblasts from patients lacking peroxisomes there is a small (25%) but significant deficiency of the ability to activate very long chain fatty acids. This deficient activity of very long chain fatty acyl-CoA synthetase is also observed in fibroblast homogenates from patients with X-linked adrenoleukodystrophy. We conclude that X-linked adrenoleukodystrophy is caused by a deficiency of peroxisomal very long chain fatty acyl-CoA synthetase.

Full text

PDF
1778

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bhushan A., Singh R. P., Singh I. Characterization of rat brain microsomal acyl-coenzyme A ligases: different enzymes for the synthesis of palmitoyl-coenzyme A and lignoceroyl-coenzyme A. Arch Biochem Biophys. 1986 Apr;246(1):374–380. doi: 10.1016/0003-9861(86)90482-0. [DOI] [PubMed] [Google Scholar]
  2. Bremer J., Norum K. R. Metabolism of very long-chain monounsaturated fatty acids (22:1) and the adaptation to their presence in the diet. J Lipid Res. 1982 Feb;23(2):243–256. [PubMed] [Google Scholar]
  3. DE DUVE C., PRESSMAN B. C., GIANETTO R., WATTIAUX R., APPELMANS F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955 Aug;60(4):604–617. doi: 10.1042/bj0600604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Datta N. S., Wilson G. N., Hajra A. K. Deficiency of enzymes catalyzing the biosynthesis of glycerol-ether lipids in Zellweger syndrome. A new category of metabolic disease involving the absence of peroxisomes. N Engl J Med. 1984 Oct 25;311(17):1080–1083. doi: 10.1056/NEJM198410253111704. [DOI] [PubMed] [Google Scholar]
  5. Goldfischer S., Collins J., Rapin I., Coltoff-Schiller B., Chang C. H., Nigro M., Black V. H., Javitt N. B., Moser H. W., Lazarow P. B. Peroxisomal defects in neonatal-onset and X-linked adrenoleukodystrophies. Science. 1985 Jan 4;227(4682):67–70. doi: 10.1126/science.3964959. [DOI] [PubMed] [Google Scholar]
  6. Goldfischer S., Reddy J. K. Peroxisomes (microbodies) in cell pathology. Int Rev Exp Pathol. 1984;26:45–84. [PubMed] [Google Scholar]
  7. Hashmi M., Stanley W., Singh I. Lignoceroyl-CoASH ligase: enzyme defect in fatty acid beta-oxidation system in X-linked childhood adrenoleukodystrophy. FEBS Lett. 1986 Feb 17;196(2):247–250. doi: 10.1016/0014-5793(86)80256-3. [DOI] [PubMed] [Google Scholar]
  8. Heymans H. S., vd Bosch H., Schutgens R. B., Tegelaers W. H., Walther J. U., Müller-Höcker J., Borst P. Deficiency of plasmalogens in the cerebro-hepato-renal (Zellweger) syndrome. Eur J Pediatr. 1984 Apr;142(1):10–15. doi: 10.1007/BF00442582. [DOI] [PubMed] [Google Scholar]
  9. Kelley R. I., Datta N. S., Dobyns W. B., Hajra A. K., Moser A. B., Noetzel M. J., Zackai E. H., Moser H. W. Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes. Am J Med Genet. 1986 Apr;23(4):869–901. doi: 10.1002/ajmg.1320230404. [DOI] [PubMed] [Google Scholar]
  10. Kelley R. I. Review: the cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet. 1983 Dec;16(4):503–517. doi: 10.1002/ajmg.1320160409. [DOI] [PubMed] [Google Scholar]
  11. Krisans S. K., Mortensen R. M., Lazarow P. B. Acyl-CoA synthetase in rat liver peroxisomes. Computer-assisted analysis of cell fractionation experiments. J Biol Chem. 1980 Oct 25;255(20):9599–9607. [PubMed] [Google Scholar]
  12. Lazarow P. B. Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol. 1981;72:315–319. doi: 10.1016/s0076-6879(81)72021-4. [DOI] [PubMed] [Google Scholar]
  13. Lazarow P. B., Black V., Shio H., Fujiki Y., Hajra A. K., Datta N. S., Bangaru B. S., Dancis J. Zellweger syndrome: biochemical and morphological studies on two patients treated with clofibrate. Pediatr Res. 1985 Dec;19(12):1356–1364. doi: 10.1203/00006450-198512000-00030. [DOI] [PubMed] [Google Scholar]
  14. Lazarow P. B., De Duve C. A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug. Proc Natl Acad Sci U S A. 1976 Jun;73(6):2043–2046. doi: 10.1073/pnas.73.6.2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lazarow P. B. Rat liver peroxisomes catalyze the beta oxidation of fatty acids. J Biol Chem. 1978 Mar 10;253(5):1522–1528. [PubMed] [Google Scholar]
  16. Leighton F., Poole B., Beaufay H., Baudhuin P., Coffey J. W., Fowler S., De Duve C. The large-scale separation of peroxisomes, mitochondria, and lysosomes from the livers of rats injected with triton WR-1339. Improved isolation procedures, automated analysis, biochemical and morphological properties of fractions. J Cell Biol. 1968 May;37(2):482–513. doi: 10.1083/jcb.37.2.482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mannaerts G. P., Debeer L. J., Thomas J., De Schepper P. J. Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats. J Biol Chem. 1979 Jun 10;254(11):4585–4595. [PubMed] [Google Scholar]
  18. Mannaerts G. P., Van Veldhoven P., Van Broekhoven A., Vandebroek G., Debeer L. J. Evidence that peroxisomal acyl-CoA synthetase is located at the cytoplasmic side of the peroxisomal membrane. Biochem J. 1982 Apr 15;204(1):17–23. doi: 10.1042/bj2040017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miyazawa S., Hashimoto T., Yokota S. Identity of long-chain acyl-coenzyme A synthetase of microsomes, mitochondria, and peroxisomes in rat liver. J Biochem. 1985 Sep;98(3):723–733. doi: 10.1093/oxfordjournals.jbchem.a135330. [DOI] [PubMed] [Google Scholar]
  20. Moser H. W., Moser A. B., Frayer K. K., Chen W., Schulman J. D., O'Neill B. P., Kishimoto Y. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology. 1981 Oct;31(10):1241–1249. doi: 10.1212/wnl.31.10.1241. [DOI] [PubMed] [Google Scholar]
  21. Moser H. W., Moser A. B., Kawamura N., Murphy J., Suzuki K., Schaumburg H., Kishimoto Y. Adrenoleukodystrophy: elevated C26 fatty acid in cultured skin fibroblasts. Ann Neurol. 1980 Jun;7(6):542–549. doi: 10.1002/ana.410070607. [DOI] [PubMed] [Google Scholar]
  22. Moser H. W., Moser A. E., Singh I., O'Neill B. P. Adrenoleukodystrophy: survey of 303 cases: biochemistry, diagnosis, and therapy. Ann Neurol. 1984 Dec;16(6):628–641. doi: 10.1002/ana.410160603. [DOI] [PubMed] [Google Scholar]
  23. Moser H. W. Peroxisomal disorders. J Pediatr. 1986 Jan;108(1):89–91. doi: 10.1016/s0022-3476(86)80774-0. [DOI] [PubMed] [Google Scholar]
  24. Ogier H., Roels F., Cornelis A., Poll The B. T., Scotto J. M., Odievre M., Sandubray J. M. Absence of hepatic peroxisomes in a case of infantile Refsum's disease. Scand J Clin Lab Invest. 1985 Dec;45(8):767–768. doi: 10.3109/00365518509155292. [DOI] [PubMed] [Google Scholar]
  25. Poll-The B. T., Saudubray J. M., Ogier H., Schutgens R. B., Wanders R. J., Schrakamp G., van den Bosch H., Trijbels J. M., Poulos A., Moser H. W. Infantile Refsum's disease: biochemical findings suggesting multiple peroxisomal dysfunction. J Inherit Metab Dis. 1986;9(2):169–174. doi: 10.1007/BF01799455. [DOI] [PubMed] [Google Scholar]
  26. Powers J. M. Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin Neuropathol. 1985 Sep-Oct;4(5):181–199. [PubMed] [Google Scholar]
  27. Roels F., Cornelis A., Poll-The B. T., Aubourg P., Ogier H., Scotto J., Saudubray J. M. Hepatic peroxisomes are deficient in infantile refsum disease: a cytochemical study of 4 cases. Am J Med Genet. 1986 Oct;25(2):257–271. doi: 10.1002/ajmg.1320250210. [DOI] [PubMed] [Google Scholar]
  28. Schrakamp G., Roosenboom C. F., Schutgens R. B., Wanders R. J., Heymans H. S., Tager J. M., van den Bosch H. Alkyl dihydroxyacetone phosphate synthase in human fibroblasts and its deficiency in Zellweger syndrome. J Lipid Res. 1985 Jul;26(7):867–873. [PubMed] [Google Scholar]
  29. Schram A. W., Strijland A., Hashimoto T., Wanders R. J., Schutgens R. B., van den Bosch H., Tager J. M. Biosynthesis and maturation of peroxisomal beta-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum disease. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6156–6158. doi: 10.1073/pnas.83.16.6156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schutgens R. B., Heymans H. S., Wanders R. J., van den Bosch H., Tager J. M. Peroxisomal disorders: a newly recognised group of genetic diseases. Eur J Pediatr. 1986 Feb;144(5):430–440. doi: 10.1007/BF00441734. [DOI] [PubMed] [Google Scholar]
  31. Schutgens R. B., Romeyn G. J., Wanders R. J., van den Bosch H., Schrakamp G., Heymans H. S. Deficiency of acyl-CoA: dihydroxyacetone phosphate acyltransferase in patients with Zellweger (cerebro-hepato-renal) syndrome. Biochem Biophys Res Commun. 1984 Apr 16;120(1):179–184. doi: 10.1016/0006-291x(84)91430-x. [DOI] [PubMed] [Google Scholar]
  32. Scotto J. M., Hadchouel M., Odievre M., Laudat M. H., Saudubray J. M., Dulac O., Beucler I., Beaune P. Infantile phytanic acid storage disease, a possible variant of Refsum's disease: three cases, including ultrastructural studies of the liver. J Inherit Metab Dis. 1982;5(2):83–90. doi: 10.1007/BF01799998. [DOI] [PubMed] [Google Scholar]
  33. Shindo Y., Hashimoto T. Acyl-Coenzyme A synthetase and fatty acid oxidation in rat liver peroxisomes. J Biochem. 1978 Nov;84(5):1177–1181. doi: 10.1093/oxfordjournals.jbchem.a132234. [DOI] [PubMed] [Google Scholar]
  34. Singh H., Poulos A. A comparative study of stearic and lignoceric acid oxidation by human skin fibroblasts. Arch Biochem Biophys. 1986 Oct;250(1):171–179. doi: 10.1016/0003-9861(86)90714-9. [DOI] [PubMed] [Google Scholar]
  35. Singh I., Moser A. E., Goldfischer S., Moser H. W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4203–4207. doi: 10.1073/pnas.81.13.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Suzuki Y., Orii T., Mori M., Tatibana M., Hashimoto T. Deficient activities and proteins of peroxisomal beta-oxidation enzymes in infants with Zellweger syndrome. Clin Chim Acta. 1986 Apr 30;156(2):191–196. doi: 10.1016/0009-8981(86)90152-x. [DOI] [PubMed] [Google Scholar]
  37. Tager J. M., Van der Beek W. A., Wanders R. J., Hashimoto T., Heymans H. S., Van den Bosch H., Schutgens R. B., Schram A. W. Peroxisomal beta-oxidation enzyme proteins in the Zellweger syndrome. Biochem Biophys Res Commun. 1985 Feb 15;126(3):1269–1275. doi: 10.1016/0006-291x(85)90322-5. [DOI] [PubMed] [Google Scholar]
  38. Wanders R. J., Kos M., Roest B., Meijer A. J., Schrakamp G., Heymans H. S., Tegelaers W. H., van den Bosch H., Schutgens R. B., Tager J. M. Activity of peroxisomal enzymes and intracellular distribution of catalase in Zellweger syndrome. Biochem Biophys Res Commun. 1984 Sep 28;123(3):1054–1061. doi: 10.1016/s0006-291x(84)80240-5. [DOI] [PubMed] [Google Scholar]
  39. Wanders R. J., Schutgens R. B., Schrakamp G., Tager J. M., Van den Bosch H., Moser A. B., Moser H. W. Neonatal adrenoleukodystrophy. Impaired plasmalogen biosynthesis and peroxisomal beta-oxidation due to a deficiency of catalase-containing particles (peroxisomes) in cultured skin fibroblasts. J Neurol Sci. 1987 Feb;77(2-3):331–340. doi: 10.1016/0022-510x(87)90132-8. [DOI] [PubMed] [Google Scholar]
  40. Wanders R. J., Schutgens R. B., Schrakamp G., van den Bosch H., Tager J. M., Schram A. W., Hashimoto T., Poll-Thé B. T., Saudubrau J. M. Infantile Refsum disease: deficiency of catalase-containing particles (peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal beta-oxidation enzyme proteins. Eur J Pediatr. 1986 Aug;145(3):172–175. doi: 10.1007/BF00446057. [DOI] [PubMed] [Google Scholar]
  41. Wanders R. J., Smit W., Heymans H. S., Schutgens R. B., Barth P. G., Schierbeek H., Smit G. P., Berger R., Przyrembel H., Eggelte T. A. Age-related accumulation of phytanic acid in plasma from patients with the cerebro-hepato-renal (Zellweger) syndrome. Clin Chim Acta. 1987 Jun 30;166(1):45–56. doi: 10.1016/0009-8981(87)90193-8. [DOI] [PubMed] [Google Scholar]
  42. Wanders R. J., van Roermund C. W., de Vries C. T., van den Bosch H., Schrakamp G., Tager J. M., Schram A. W., Schutgens R. B. Peroxisomal beta-oxidation of palmitoyl-CoA in human liver homogenates and its deficiency in the cerebro-hepato-renal (Zellweger) syndrome. Clin Chim Acta. 1986 Aug 30;159(1):1–10. doi: 10.1016/0009-8981(86)90160-9. [DOI] [PubMed] [Google Scholar]
  43. Wanders R. J., van Roermund C. W., van Wijland M. J., Schutgens R. B., Schram A. W., van den Bosch H., Tager J. M. Studies on the peroxisomal oxidation of palmitate and lignocerate in rat liver. Biochim Biophys Acta. 1987 May 13;919(1):21–25. doi: 10.1016/0005-2760(87)90213-x. [DOI] [PubMed] [Google Scholar]
  44. Wattiaux R., Wattiaux-De Coninck S., Ronveaux-dupal M. F., Dubois F. Isolation of rat liver lysosomes by isopycnic centrifugation in a metrizamide gradient. J Cell Biol. 1978 Aug;78(2):349–368. doi: 10.1083/jcb.78.2.349. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES