Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2) - Promoter analysis and role of the peroxisome proliferator-activated receptor PPAR alpha

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease due to a defect in the ABCD1 (ALD) gene. ABCD1, and the two close homologues ABCD 2 (ALDR) and ABCD3 (PMP70), are genes encoding ATP-binding cassette half-tr ansporters of the peroxisomal membrane. As overexpression of the ABCD2 or A BCD3 gene can reverse the biochemical phenotype of X-ALD (reduced beta -oxi dation of very-long-chain fatty acids), pharmacological induction of these partially redundant genes may represent a therapeutic approach to X-ALD. We previously reported that the ABCD2 and ABCD3 genes could be strongly induc ed by fibrates, which are hypolipidaemic drugs and peroxisome-proliferators in rodents. We provide evidence that the induction is dependent on peroxis ome proliferator-activated receptor (PPAR alpha) as both genes were not ind uced in fenofibrate-treated PPAR alpha -/- knock-out mice. To further chara cterize the PPAR alpha pathway, we cloned and analysed the promoter of the ABCD2 gene, the closest homologue of the ABCD1 gene. The proximal region (2 kb) of the rat promoter displayed a high conservation with the human and m ouse cognate sequences suggesting an important role of the region in regula tion of the ABCD2 gene. Classically, fibrate-induction involves interaction of PPAR alpha with a response element (PPRE) characterized by a direct rep eat of the AGGTCA-like motif. Putative PPRE motifs of the rat ABCD2 promote r were studied in the isolated form or in their promoter context by gel-shi ft assay and transfection of COS-7 cells. We failed to characterize a funct ional PPRE, suggesting a different mechanism for the PPAR alpha -dependent regulation of the ABCD2 gene.