Fibrate induction of the adrenoleukodystrophyârelated gene (ABCD2): Promoter analysis and role of the peroxisome proliferatorâactivated receptor PPARα
2001
Fourcade, Stéphane | Savary, Stéphane | Albet, Sabrina | Gauthé, Delphine | Gondcaille, Catherine | Pineau, Thierry | Bellenger, Jérome | Bentejac, Marc | Holzinger, Andreas | Berger, Johannes | Bugaut, Maurice
Xâlinked adrenoleukodystrophy (XâALD) is a neurodegenerative disease due to a defect in the ABCD1 (ALD) gene. ABCD1, and the two close homologues ABCD2 (ALDR) and ABCD3 (PMP70), are genes encoding ATPâbinding cassette halfâtransporters of the peroxisomal membrane. As overexpression of the ABCD2 or ABCD3 gene can reverse the biochemical phenotype of XâALD (reduced βâoxidation of veryâlongâchain fatty acids), pharmacological induction of these partially redundant genes may represent a therapeutic approach to XâALD. We previously reported that the ABCD2 and ABCD3 genes could be strongly induced by fibrates, which are hypolipidaemic drugs and peroxisomeâproliferators in rodents. We provide evidence that the induction is dependent on peroxisome proliferatorâactivated receptor (PPARα) as both genes were not induced in fenofibrateâtreated PPARα–/– knockâout mice. To further characterize the PPARα pathway, we cloned and analysed the promoter of the ABCD2 gene, the closest homologue of the ABCD1 gene. The proximal region (2âkb) of the rat promoter displayed a high conservation with the human and mouse cognate sequences suggesting an important role of the region in regulation of the ABCD2 gene. Classically, fibrateâinduction involves interaction of PPARα with a response element (PPRE) characterized by a direct repeat of the AGGTCAâlike motif. Putative PPRE motifs of the rat ABCD2 promoter were studied in the isolated form or in their promoter context by gelâshift assay and transfection of COSâ7 cells. We failed to characterize a functional PPRE, suggesting a different mechanism for the PPARαâdependent regulation of the ABCD2 gene.
Show more [+] Less [-]AGROVOC Keywords
Bibliographic information
This bibliographic record has been provided by National Agricultural Library