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X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the  ABCD1  gene that encodes the peroxisomal ATP-binding cassette (ABC) transporter subfamily D member 1 protein (ABCD1), which is referred to as the adrenoleukodystrophy protein (ALDP). Induction of the  ABCD2  gene, the closest homolog of  ABCD1 , has been mentioned as a possible therapeutic option for the defective ABCD1 protein in X-ALD. However, little is known about the transcriptional regulation of  ABCD2  gene expression. Here, through in silico analysis, we found two putative TCF-4 binding elements between nucleotide positions −360 and −260 of the promoter region of the  ABCD2  gene. The transcriptional activity of the  ABCD2  promoter was strongly increased by ectopic expression of  β -catenin and TCF-4. In addition, mutation of either or both TCF-4 binding elements by site-directed mutagenesis decreased promoter activity. This was further validated by the finding that  β -catenin and the promoter of the  ABCD2  gene were pulled down with a  β -catenin antibody in a chromatin immunoprecipitation assay. Moreover, real-time PCR analysis revealed that  β -catenin and TCF-4 increased mRNA levels of  ABCD2  in both a hepatocellular carcinoma cell line and primary fibroblasts from an X-ALD patient. Interestingly, we found that the levels of very long chain fatty acids were decreased by ectopic expression of ABCD2-GFP as well as  β -catenin and TCF-4. Taken together, our results demonstrate for the first time the direct regulation of  ABCD2  by  β -catenin and TCF-4.

ABCD2 Is a Direct Target of β-Catenin and TCF-4: Implications for X-Linked Adrenoleukodystrophy Therapy