title: Evaluation of pharmacological induction of fatty acid beta-oxidation in X-linked adrenoleukodystrophy.
abstract: 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 beta-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 beta-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 beta-oxidation in ALD mouse fibroblasts is tested. 4PBA, styrylacetate and benzyloxyacetate (structurally related to 4PBA), and trichostatin A (functionally related to 4PBA) increase both VLCFA (peroxisomal) and long-chain fatty acid [LCFA (peroxisomal and mitochondrial)] beta-oxidation. Isobutyrate, zaprinast, hydroxyurea, and 5-azacytidine had no effect on VLCFA or LCFA beta-oxidation. Lovastatin had no effect on fatty acid beta-oxidation under normal tissue culture conditions but did result in an increase in both VLCFA and LCFA beta-oxidation when ALD mouse fibroblasts were cultured in the absence of cholesterol. The effect of trichostatin A on peroxisomal VLCFA beta-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.
authors.affiliation: Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. mcmcguin@jhmi.edu
authors.forename: M C
authors.initials: MC
authors.lastname: McGuinness
authors.forename: H P
authors.initials: HP
authors.lastname: Zhang
authors.forename: K D
authors.initials: KD
authors.lastname: Smith
mesh_terms: D000326:Adrenoleukodystrophy / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D010654:Phenylbutyrates / Q000494:pharmacology; D014960:X Chromosome / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010654:Phenylbutyrates; C012589:trichostatin A; C075773:4-phenylbutyric acid; D008148:Lovastatin