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Published online 4 April 2005. doi:10.1083/jcb.200501036
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 169, Number 1, 93-104
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Article

 Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator

Catherine Gondcaille1, Marianne Depreter2, Stéphane Fourcade1, Maria Rita Lecca1, Sabrina Leclercq1, Pascal G.P. Martin3, Thierry Pineau3, Françoise Cadepond4, Martine ElEtr4, Nathalie Bertrand5, Alain Beley5, Sandrine Duclos1, Dirk De Craemer2, Frank Roels2, Stéphane Savary1, and Maurice Bugaut1

1 Laboratoire de Biologie Moléculaire et Cellulaire, Faculté des Sciences Gabriel, 21000 Dijon, France
2 Department of Human Anatomy, Embryology, Histology and Medical Physics, Ghent University, 9000 Gent, Belgium
3 Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, 31931 Toulouse, France
4 Institut National de la Santé et de la Recherche Médicale U488, 94276 Le Kremlin-Bicêtre, France
5 Laboratoire de Pharmacodynamie, Faculté de Pharmacie, 21000 Dijon, France

Correspondence to Stéphane Savary: stsavary{at}u-bourgogne.fr

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPAR{alpha}-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPAR{alpha} independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition.

Dr. Bugaut died on 16 September 2004.

M. Depreter's present address is Institute for Stem Cell Research, University of Edinburgh, Edinburgh EH9 3JQ, UK.

Abbreviations used in this paper: AOX, acyl-CoA oxidase; DAPA, DNA affinity precipitation assay; EMSA, electrophoretic mobility shift assay; HAT, histone acetyl transferase; HDAC, histone deacetylase; LM, light microscopy; PBA, 4-phenylbutyrate; PP, peroxisome proliferator; TSA, trichostatin A; VLCFA, very long-chain fatty acids; X-ALD, X-linked adrenoleukodystrophy.


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