Evaluation of pharmacological induction of fatty acid β-oxidation in X-linked adrenoleukodystrophy

M. C. McGuinness, H. P. Zhang, K. D. Smith

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder associated with elevated levels of saturated unbranched very-long-chain fatty acids (VLCFA; C>22:0) in plasma and tissues, and reduced VLCFA β-oxidation in fibroblasts, white blood cells, and amniocytes from X-ALD patients. The X-ALD gene (ABCD1) at Xq28 encodes the adrenoleukodystrophy protein (ALDP) that is related to the peroxisomal ATP-binding cassette (ABCD) transmembrane half-transporter proteins. The function of ALDP is unknown and its role in VLCFA accumulation unresolved. Previously, our laboratory has shown that sodium 4-phenylbutyrate (4PBA) treatment of X-ALD fibroblasts results in increased peroxisomal VLCFA β-oxidation activity and increased expression of the X-ALD-related protein, ALDRP, encoded by the ABCD2 gene. In this study, the effect of various pharmacological agents on VLCFA β-oxidation in ALD mouse fibroblasts is tested. 4PBA, styrylacetate and benzyloxy-acetate (structurally related to 4PBA), and trichostatin A (functionally related to 4PBA) increase both VLCFA (peroxisomal) and long-chain fatty acid [LCFA (peroxisomal and mitochondrial)] β-oxidation. Isobutyrate, zaprinast, hydroxyurea, and 5-azacytidine had no effect on VLCFA or LCFA β-oxidation. Lovastatin had no effect on fatty acid β-oxidation under normal tissue culture conditions but did result in an increase in both VLCFA and LCFA β-oxidation when ALD mouse fibroblasts were cultured in the absence of cholesterol. The effect of trichostatin A on peroxisomal VLCFA β-oxidation is shown to be independent of an increase in ALDRP expression, suggesting that correction of the biochemical abnormality in X-ALD is not dependent on pharmacological induction of a redundant gene (ABCD2). These studies contribute to a better understanding of the role of ALDP in VLCFA accumulation and may lead to the development of more effective pharmacological therapies.

Original languageEnglish (US)
Pages (from-to)256-263
Number of pages8
JournalMolecular genetics and metabolism
Issue number1-2
StatePublished - 2001


  • Fatty acid β-oxidation
  • Pharmacological agents
  • Therapy
  • X-linked adrenoleukodystrophy

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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