Inherited defects in the peroxisomal ATP-binding cassette (ABC) transporter adrenoleukodystrophy protein (ALDP) lead to the lethal peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD), for which no efficient treatment has been established so far. Three other peroxisomal ABC transporters currently are known: adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxisomal membrane protein (PMP70) and PMP70- related protein. By using transient and stable overexpression of human cDNAs encoding ALDP and its closest relative ALDRP, we could restore the impaired peroxisomal beta-oxidation in fibroblasts of X-ALD patients. The pathognomonic accumulation of very long chain fatty acids could also be prevented by overexpression of ALDRP in immortalized X-ALD cells. Immunofluorescence analysis demonstrated that the functional replacement of ALDP by ALDRP was not due to stabilization of the mutated ALDP itself. Moreover, we were able to restore the peroxisomal beta-oxidation defect in the liver of ALDP-deficient mice by stimulation of ALDRP and PMP70 gene expression through a dietary treatment with the peroxisome proliferator fenofibrate. These results suggest that a correction of the biochemical defect in X-ALD could be possible by drug-induced overexpression or ectopic expression of ALDRP.
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 b-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 H 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.Keywords: adrenoleukodystrophy; ATP-binding cassette transporter; fenofibrate; gene expression; peroxisome.Four ABC-transporters have been identified in the mammalian peroxisomal membrane: adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), 70 kDa peroxisomal membrane protein (PMP70) and PMP70-related protein (P70R/PMP69). Relative to ALDP the human proteins display 63%, 36%, and 25% amino acid identity [1], respectively, and all have the predicted structure of a half-transporter with one membrane spanning domain and one nucleotide binding fold. As most of the half-transporters identified to date function as dimers, it has been suggested that the peroxisomal ABCtransporters also need to assemble as homo-or heterodimers in order to form a functional unit [2,3].Although the exact functions and substrates of the mammalian peroxisomal ABC-transporters have yet to be defined, the detrimental effects of a deficient transporter is demonstrated by mutations in the ALD gene, leading to the lipid storage disorder X-linked adrenoleukodystrophy (X-ALD, McKusick #300100). Biochemically X-ALD is characterized by defective peroxisomal b-oxidation of sat...
The uptake as well as the export of citric acid by Aspergillus niger occur by active, deltapH-driven, H(+)-symport dependent systems. They are inhibited by nonmetabolizable tricarboxylic acid analogues and phthalic acid, and by several other mono-, di- and tribasic organic acids. However, citrate export could only be demonstrated in a mycelium cultivated under manganese-deficient growth conditions, whereas the uptake of citrate from the medium was only detectable upon precultivation of A. niger in a medium supplemented with Mn2+ ions. In addition, the uptake of citrate was dependent on the presence of Mn2+ ions in the assay, and inhibited by EDTA. This requirement for Mn2+ could also be partially fulfilled by Mg2+, Fe2+ or Zn2+, whereas Cu2+ ions inhibited citrate transport. The observed divergent effects of manganese ions on citrate uptake and citrate export may be a major reason for the well documented requirement for manganese deficiency of citric acid accumulation.
X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disorder associated with impaired very-long-chain fatty-acid (VL-CFA) -oxidation caused by mutations in the ABCD1 (ALD) gene that encodes a peroxisomal membrane ABC transporter. ABCD2 (ALDR) displays partial functional redundancy because when overexpressed, it is able to correct the X-ALD biochemical phenotype. The ABCD2 promoter contains a putative thyroid hormone-response element conserved in rodents and humans. In this report, we demonstrate that the element is capable of binding retinoid X receptor and 3,5,3Ј-tri-iodothyronine (T 3 ) receptor (TR) as a heterodimer and mediating T 3 responsiveness of ABCD2 in its promoter context. After a T 3 treatment, an induction of the ABCD2 gene was observed in the liver of normal rats but not that of TRϪ/Ϫ mice. ABCD2 was not induced in the brain of the T 3 -treated rats. However, we report for the first time that induction of the ABCD2 redundant gene is feasible in myelin-producing cells (differentiated CG4 oligodendrocytes). The induction was specific for this cell type because it did not occur in astrocytes. Furthermore, we observed T 3 induction of ABCD2 in human and mouse ABCD1-deficient fibroblasts, which was correlated with normalization of the VLCFA -oxidation. Finally, ABCD3 (PMP70), a close homolog of ABCD2, was also induced by T 3 in the liver of control rats, but not that of TRϪ/Ϫ mice, and in CG4 oligodendrocytes.
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