Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics.
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 (ALD) gene. The ABCD2 gene, its closest homolog, has been shown to compensate for ABCD1 deficiency when overexpressed. We previously demonstrated that the ABCD2 promoter contains a functional thyroid hormone response element. Thyroid hormone (T3) through its receptor TRbeta can induce hepatic Abcd2 expression in rodents and transiently normalize the VLCFA level in fibroblasts of Abcd1 null mice. In a therapeutic perspective, the use of selective agonists of TRbeta should present the advantage to be devoid of side effects, at least concerning the cardiotoxicity associated to TRalpha activation. In this study, we compared the effects of T3 with those of two thyromimetics (GC-1 and CGS 23425) specific of TRbeta. Using a gene reporter assay, we demonstrated that the rat Abcd2 promoter responds to the thyromimetics in a dose-dependent way similar to what is observed with T3. We then investigated the effects of 2-, 4- and 10-day treatments on the expression of ABCD2 and its paralogs ABCD3 and ABCD4 in human cell lines by RT-qPCR. Both thyromimetics trigger up-regulation of ABCD2-4 genes in HepG2 cells and X-ALD fibroblasts. Interestingly, in X-ALD fibroblasts, while T3 is associated with a transient induction of ABCD2 and ABCD3, the treatments with thyromimetics allow the induction to be maintained until 10 days. Further in vivo experiments in Abcd1 null mice with these thyromimetics should confirm the therapeutic potentialities of these molecules.
Genin
Emmanuelle C
EC
INSERM, U866, Dijon, F-21000, France.
Gondcaille
Catherine
C
Trompier
Doriane
D
Savary
Stéphane
S
D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000085:Acetates / Q000494:pharmacology*; D000326:Adrenoleukodystrophy / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006038:Glyoxylates / Q000494:pharmacology*; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D013963:Thyroid Hormones / Q000494:pharmacology*; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
C431694:ABCD2 protein, human; C063305:ABCD3 protein, human; C489273:ABCD4 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; C525916:Abcd2 protein, rat; D000085:Acetates; C108180:CGS 23425; C413355:GC 1 compound; D006038:Glyoxylates; D010636:Phenols; D013963:Thyroid Hormones; D014284:Triiodothyronine