Thyroid hormone induction of the adrenoleukodystrophy-related gene (ABCD2).
X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disorder associated with impaired very-long-chain fatty-acid (VLCFA) beta-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 3,5,3'-tri-iodothyronine (T3) receptor (TRbeta) as a heterodimer and mediating T3 responsiveness of ABCD2 in its promoter context. After a T3 treatment, an induction of the ABCD2 gene was observed in the liver of normal rats but not that of TRbeta-/- mice. ABCD2 was not induced in the brain of the T3-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 T3 induction of ABCD2 in human and mouse ABCD1-deficient fibroblasts, which was correlated with normalization of the VLCFA beta-oxidation. Finally, ABCD3 (PMP70), a close homolog of ABCD2, was also induced by T3 in the liver of control rats, but not that of TRbeta-/- mice, and in CG4 oligodendrocytes.
Fourcade
Stéphane
S
Laboratoire de Biologie Moléculaire et Cellulaire, Faculté des Sciences Gabriel, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France.
Savary
Stéphane
S
Gondcaille
Catherine
C
Berger
Johannes
J
Netik
Angela
A
Cadepond
Françoise
F
El Etr
Martine
M
Molzer
Brunhilde
B
Bugaut
Maurice
M
D000326:Adrenoleukodystrophy / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D013963:Thyroid Hormones / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism; D014284:Triiodothyronine / Q000502:physiology*; D015854:Up-Regulation
C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515483:Ccl22 protein, mouse; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D013963:Thyroid Hormones; D014157:Transcription Factors; D014284:Triiodothyronine