Lignoceric acid is oxidized in the peroxisome: Implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy

I. Singh, Ann B. Moser, S. Goldfischer, H. W. Moser

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Abstract

The deficient oxidation and accumulation of very-long-chain fatty acids in the Zellweger cerebro-hepatorenal syndrome (CHRS) and X chromosome-linked adrenoleukodystrophy (ALD), coupled with the observation that peroxisomes are lacking in CHRS, prompted us to investigate the subcellular localization of the catabolism of lignoceric acid (C24:0). Peroxisomal and mitochondrial-rich fractions were separated from rat liver crude mitochondria by sucrose density gradient centrifugation. Enzyme activity for the oxidation of [1-14C]palmitic acid to water-soluble acetate was 2- to 3-fold higher in the mitochondrial than in the peroxisomal-rich fraction whereas [1-14C]lignoceric acid was oxidized at a 2- to 3-fold higher rate in the peroxisomal than in the mitochondrial fraction. Moreover, unlike palmitic acid oxidation, lignoceric acid oxidation was not inhibited by potassium cyanide in either rat liver fractions or human skin cultured fibroblasts, showing that lignoceric acid is mainly and possibly exclusively oxidized in peroxisomes. We also conducted studies to clarify the striking phenotypic differences between CHRS and the childhood form of ALD. In contrast to CHRS, we found normal hepatocellular peroxisomes in the liver biopsy of a childhood ALD patient. In addition, in the presence of potassium cyanide, the oxidation of palmitic acid in cultured skin fibroblasts was inhibited by 62% in control and X chromosome-linked ALD patients compared with 88% in CHRS and neonatal ALD. This differential effect may be related to differences in peroxisomal morphology in those disorders.

Original languageEnglish (US)
Pages (from-to)4203-4207
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume81
Issue number13 I
StatePublished - 1984

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Zellweger Syndrome
Adrenoleukodystrophy
Hepatorenal Syndrome
Peroxisomes
Palmitic Acid
Potassium Cyanide
X Chromosome
Fibroblasts
Peroxisomal Disorders
Skin
Density Gradient Centrifugation
Liver Mitochondrion
Liver
Sucrose
Acetates
Fatty Acids
lignoceric acid
Biopsy
Water
Enzymes

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

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title = "Lignoceric acid is oxidized in the peroxisome: Implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy",
abstract = "The deficient oxidation and accumulation of very-long-chain fatty acids in the Zellweger cerebro-hepatorenal syndrome (CHRS) and X chromosome-linked adrenoleukodystrophy (ALD), coupled with the observation that peroxisomes are lacking in CHRS, prompted us to investigate the subcellular localization of the catabolism of lignoceric acid (C24:0). Peroxisomal and mitochondrial-rich fractions were separated from rat liver crude mitochondria by sucrose density gradient centrifugation. Enzyme activity for the oxidation of [1-14C]palmitic acid to water-soluble acetate was 2- to 3-fold higher in the mitochondrial than in the peroxisomal-rich fraction whereas [1-14C]lignoceric acid was oxidized at a 2- to 3-fold higher rate in the peroxisomal than in the mitochondrial fraction. Moreover, unlike palmitic acid oxidation, lignoceric acid oxidation was not inhibited by potassium cyanide in either rat liver fractions or human skin cultured fibroblasts, showing that lignoceric acid is mainly and possibly exclusively oxidized in peroxisomes. We also conducted studies to clarify the striking phenotypic differences between CHRS and the childhood form of ALD. In contrast to CHRS, we found normal hepatocellular peroxisomes in the liver biopsy of a childhood ALD patient. In addition, in the presence of potassium cyanide, the oxidation of palmitic acid in cultured skin fibroblasts was inhibited by 62{\%} in control and X chromosome-linked ALD patients compared with 88{\%} in CHRS and neonatal ALD. This differential effect may be related to differences in peroxisomal morphology in those disorders.",
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T1 - Lignoceric acid is oxidized in the peroxisome

T2 - Implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy

AU - Singh, I.

AU - Moser, Ann B.

AU - Goldfischer, S.

AU - Moser, H. W.

PY - 1984

Y1 - 1984

N2 - The deficient oxidation and accumulation of very-long-chain fatty acids in the Zellweger cerebro-hepatorenal syndrome (CHRS) and X chromosome-linked adrenoleukodystrophy (ALD), coupled with the observation that peroxisomes are lacking in CHRS, prompted us to investigate the subcellular localization of the catabolism of lignoceric acid (C24:0). Peroxisomal and mitochondrial-rich fractions were separated from rat liver crude mitochondria by sucrose density gradient centrifugation. Enzyme activity for the oxidation of [1-14C]palmitic acid to water-soluble acetate was 2- to 3-fold higher in the mitochondrial than in the peroxisomal-rich fraction whereas [1-14C]lignoceric acid was oxidized at a 2- to 3-fold higher rate in the peroxisomal than in the mitochondrial fraction. Moreover, unlike palmitic acid oxidation, lignoceric acid oxidation was not inhibited by potassium cyanide in either rat liver fractions or human skin cultured fibroblasts, showing that lignoceric acid is mainly and possibly exclusively oxidized in peroxisomes. We also conducted studies to clarify the striking phenotypic differences between CHRS and the childhood form of ALD. In contrast to CHRS, we found normal hepatocellular peroxisomes in the liver biopsy of a childhood ALD patient. In addition, in the presence of potassium cyanide, the oxidation of palmitic acid in cultured skin fibroblasts was inhibited by 62% in control and X chromosome-linked ALD patients compared with 88% in CHRS and neonatal ALD. This differential effect may be related to differences in peroxisomal morphology in those disorders.

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