The four murine peroxisomal ABC-transporter genes differ in constitutive, inducible and developmental expression

Abstract

Four ATP-binding cassette (ABC) half-transporters have been identified in mammalian peroxisomes: adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), 70-kDa peroxisomal membrane protein (PMP70) and PMP70-related protein (P70R). Inherited defects in ALDP cause the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD). By comparative Northern blot analyses we found each of the four murine peroxisomal ABC transporter mRNA species at maximum abundance only in a few tissues, which differed for each family member. The four genes were also regulated differentially during mouse brain development: ALDP mRNA was most abundant in embryonic brain and gradually decreased during maturation; ALDRP and P70R mRNA accumulated in the early postnatal period; and the amount of PMP70 transcript increased slightly during the second and third postnatal week. The different expression patterns could explain why beta-oxidation is defective in X-ALD, although ALDRP and PMP70 can replace ALDP functionally in fibroblasts. Dietary fenofibrate had no effect on the ALD and P70R genes, but strongly increased expression of the ALDR and PMP70 genes in mouse liver. However, in P-glycoprotein Mdr1a-deficient mice fenofibrate treatment increased ALDR gene expression also in the brain, suggesting that the multidrug-transporter P-glycoprotein restricts entry of fenofibrate to the brain at the blood-brain barrier. Analysis of the promoter sequences revealed a cryptic nuclear hormone receptor response element of the DR+4 type in the ALDR promoter and a novel 18-bp sequence motif present only in the 5' flanking DNA of the ALDR and PMP70 genes. The mouse ALDR gene uses a single transcription start site but alternative polyadenylation sites. These data are of importance for the use of ALDP-deficient mice as a model in pharmacological gene therapy studies.