Journal of Steroid Biochemistry & Molecular Biology 116 (2009) 37–43 Contents lists available at ScienceDirect Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics Emmanuelle C. Genin a,b , Catherine Gondcaille a,b , Doriane Trompier a,b , Stéphane Savary a,b,∗ a INSERM, U866, Dijon, F-21000, France b Université de Bourgogne, Faculté des Sciences Gabriel, Centre de Recherche Lipides, Nutrition, Cancer – Laboratoire de Biochimie Métabolique et Nutritionnelle (LBMN), Dijon, F-21000, France article info Article history: Received 27 November 2008 Received in revised form 16 April 2009 Accepted 20 April 2009 Keywords: Peroxisome ABC transporters Adrenoleukodystrophy Thyroid hormone Gene expression abstract 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 TR 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 TR should present the advantage to be devoid of side effects, at least concerning the cardiotoxicity associated to TR activation. In this study, we compared the effects of T3 with those of two thyromimetics (GC-1 and CGS 23425) specific of TR. 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. © 2009 Elsevier Ltd. All rights reserved. 1. Introduction X-linked adrenoleukodystrophy (X-ALD, OMIM 300100), the most frequent genetic peroxisomal disorder, presents distinct phenotypes varying both in symptoms and onset [1,2]. The child- hood cerebral form (CCALD) and the adrenomyeloneuropathy (AMN) represent the main phenotypes. Whatever the clinical pattern, X-ALD patients display a characteristic accumulation of saturated and monounsaturated very-long-chain fatty acids (VLCFA, C > 22) in plasma and tissues. The exact link between this accumulation and the pathogenesis is still unclear mak- ing therapeutic progresses so difficult. In fact, hematopoietic stem cell transplantation is currently the only therapy for CCALD but its high risk of mortality, the difficulty to find compati- ble donors, and the need to do the transplant in early stages of the disease, lead to search for other therapeutic strate- gies. ∗ Corresponding author at: LBMN, INSERM U866, Université de Bourgogne, 6 Bd Gabriel, Dijon, F-21000, France. Tel.: +33 380396273; fax: +33 380396250. E-mail address: stsavary@u-bourgogne.fr (S. Savary). X-ALD is caused by mutations in the ABCD1 gene (for- merly called ALD) encoding for a half ABC transporter of the peroxisomal membrane [3]. ALDP, as a homodimer or as a het- erodimer with one of the three other peroxisomal ABC transporters (ALDRP, PMP70 and PMP69), is thought to import VLCFA-CoA esters into the peroxisome allowing their -oxidation. ALDRP (adrenoleukodystrophy-related protein) [4], PMP70 (70 kDa per- oxisomal membrane protein) [5] and PMP69 (69 kDa peroxisomal membrane protein) [6,7] (whose peroxisomal localization has recently been questioned [8]) are encoded respectively by the ABCD2, ABCD3 and ABCD4 genes. ABCD1 and ABCD2 (and ABCD3 to a lesser extent) have been shown to present a partial func- tional redundancy [9]. The overexpression of the ABCD2 gene in fibroblasts from X-ALD patients corrects VLCFA -oxidation [10,11]. Moreover, in Abcd1 null mice, the Abcd2 overexpression prevents VLCFA accumulation and onset of neurodegenerative phenotype [12]. We and others have shown that the Abcd2 gene is inducible in vivo by drugs, like fibrates or 4-phenyl- butyrate (4-PBA) [13–17]. Hormones such as DHEA and thyroid hormones (thyroxine (T4) and triiodothironine (T3)) can also induce Abcd2 expression [18,19]. Since this induction can prevent VLCFA accumulation and restore -oxidation in Abcd1 deficient cells and tissues [11,18], pharmacological therapy targeting the 0960-0760/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2009.04.006