The adrenoleukodystrophy-related gene (ALDR, ABCD2) is a candidate modifier gene and a potential therapeutic target for X-linked adrenoleukodystrophy (ALD), a severe neurodegenerative disease. The ALDR gene is the closest homologue of the ALD gene, which encodes a peroxisomal ABC transporter involved in the catabolism of very-long-chain fatty acids. Administration of fenofibrate upregulates ALDR expression in rodent liver. As a step toward understanding ALDR transcriptional regulation, the mouse and human 5' regions were characterized. The human and mouse genes share a 500-bp conserved region that contains potential Sp1- and AP-2-binding sites but no TATA box. Analysis of the 5'-flanking region of ALDR using a luciferase reporter system revealed that 1.3 kb of human or mouse 5'-upstream region has functional promoter activity. In these transfection experiments, promoter activity of both human and mouse genes could be upregulated by 9-cis-retinoic acid and forskolin, while no effect of PPARalpha could be detected.