Thyroid Hormone Induction of the Adrenoleukodystrophy-Related Gene (ABCD2)

Abstract

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 TR␤Ϫ/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 TR␤Ϫ/Ϫ mice, and in CG4 oligodendrocytes.

Therapy of X-linked adrenoleukodystrophy

“…These include phenylbutyrate, which has shown promising results in a mouse model of X-ALD, 52 arginine butyrate, 53 and Lovastatin. 54 Particular interest attaches to approaches that increase the expression of ABCD2, 55 a gene that maps to chromosome 12 and codes for a protein that can substitute in part for the function of ALDP, and in the long range, gene replacement therapy.…”

Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics

“…The rat Abcd2 promoter was previously demonstrated to mediate induction of luciferase reporter gene in T3-treated COS-7 cells co-transfected with TR␤1 [18]. Using the same construct, i.e., the p2206 plasmid, which contains approximately 2 kb of the rat Abcd2 promoter cloned into pGL3 (Promega), we compared the effects of different doses (1, 10, 100 or 1000 nM) of GC-1 and CGS 23425 to those of T3.…”

“…The transfected cells were incubated with or without T3, GC-1, CGS 23425 at 1, 10, 100 or 1000 nM for 48 h, and assayed for luciferase activity as previously described [15,18]. Luciferase activity was corrected according to the protein content (Bradford assay).…”

“…Thyroid hormones are known to induce peroxisomal biogenesis and ␤-oxidation [20,21] and were previously demonstrated to induce Abcd2 expression in vitro and in vivo, the Abcd2 promoter containing a functional thyroid hormone response element (TRE) [18]. These hormones exert their effects in almost all tissues and are involved in a lot of physiological processes essential for normal growth, development and metabolism (particularly lipid metabolism) [22].…”

“…We and others have shown that the Abcd2 gene is inducible in vivo by drugs, like fibrates or 4-phenylbutyrate (4-PBA) [13][14][15][16][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 induction of ABCD2 could therefore represent a potential therapeutic alternative provided that inducers are devoid of major side effects.…”