Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2)
| Autor: | Sabrina Albet, Jérome Bellenger, Johannes Berger, Stéphane Savary, Maurice Bugaut, Catherine Gondcaille, Delphine Gauthé, Andreas Holzinger, Thierry Pineau, Stéphane Fourcade, Marc Bentejac |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Transcription Genetic Molecular Sequence Data Response element Receptors Cytoplasmic and Nuclear ATP-binding cassette transporter ATP Binding Cassette Transporter Subfamily D Biochemistry Mice Fenofibrate ABCD3 Sequence Homology Nucleic Acid ABCD2 medicine Animals Humans Rats Wistar Adrenoleukodystrophy Promoter Regions Genetic Gene Hypolipidemic Agents Mice Knockout Base Sequence biology DNA Transfection Peroxisome medicine.disease Molecular biology Rats Gene Expression Regulation biology.protein ATP-Binding Cassette Transporters Transcription Factors |
| Zdroj: | European Journal of Biochemistry. 268:3490-3500 |
| ISSN: | 0014-2956 |
| DOI: | 10.1046/j.1432-1327.2001.02249.x |
| Popis: | X-linked adrenoleukodystrophy (X-ALD) 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 ATP-binding cassette half-transporters of the peroxisomal membrane. As overexpression of the ABCD2 or ABCD3 gene can reverse the biochemical phenotype of X-ALD (reduced beta-oxidation 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 induced by fibrates, which are hypolipidaemic drugs and peroxisome-proliferators in rodents. We provide evidence that the induction is dependent on peroxisome proliferator-activated receptor (PPARalpha) as both genes were not induced in fenofibrate-treated PPARalpha -/- knock-out mice. To further characterize the PPARalpha 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 mouse cognate sequences suggesting an important role of the region in regulation of the ABCD2 gene. Classically, fibrate-induction involves interaction of PPARalpha with a response element (PPRE) characterized by a direct repeat of the AGGTCA-like motif. Putative PPRE motifs of the rat ABCD2 promoter were studied in the isolated form or in their promoter context by gel-shift assay and transfection of COS-7 cells. We failed to characterize a functional PPRE, suggesting a different mechanism for the PPARalpha-dependent regulation of the ABCD2 gene. |
| Databáze: | OpenAIRE |
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