TY - JOUR
T1 - Evaluation of pharmacological induction of fatty acid β-oxidation in X-linked adrenoleukodystrophy
AU - McGuinness, M. C.
AU - Zhang, H. P.
AU - Smith, K. D.
N1 - Funding Information:
We thank Ann Moser for providing X-ALD patient cell lines. We also thank Paul Watkins and Ann Heinzer for helpful discussion and for review of the manuscript. This work was supported by Grant HD10981 from the National Institutes of Health.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Fatty acid β-oxidation
KW - Pharmacological agents
KW - Therapy
KW - X-linked adrenoleukodystrophy
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U2 - 10.1006/mgme.2001.3239
DO - 10.1006/mgme.2001.3239
M3 - Article
C2 - 11592822
AN - SCOPUS:0034798513
SN - 1096-7192
VL - 74
SP - 256
EP - 263
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
ER -