Distinct modulatory roles for thyroid hormone receptors TR alpha and TR beta in SREBP1-activated ABCD2 expression

Adrenoleukodystrophy-related protein, a peroxisomal ABC transporter encoded by ABCD2, displays functional redundancy with the disease-associated X-linked adrenoleukodystrophy protein, making pharmacological induction Of ABCD2 a potentially attractive therapeutic approach. Sterol regulatory element (SRE)-binding proteins (SREBPs) induce ABCD2 through an SRE overlapping with a direct repeat (DR-4) element. Here we show that thyroid hormone (T-3) receptor (TR)alpha and TR beta bind this motif thereby modulating SREBP1-dependent activation of ABCD2. Unliganded TR beta, but not TR alpha, represses ABCD2 induction independently of DNA binding. However, activation by TR alpha and derepression of TR beta are T-3-dependent and require intact SRE/DR-4 motifs. Electrophoretic mobility shift assays with nuclear extracts support a direct interaction of TR and SREBP1 at the SRE/DR-4. In the liver, Abcd2 expression is high in young mice (with high T-3 and TR alpha levels) but downregulated in adults (with low T-3 and TR alpha but elevated TR beta levels). This temporal repression of Abcd2 is blunted in TR beta-deficient mice, and the response to manipulated T-3 states is abrogated in TR alpha-deficient mice. These findings show that TR alpha and TR beta differentially modulate SREBP1-activated ABCD2 expression at overlapping SRE/DR-4 elements, suggesting a novel mode of cross-talk between TR and SREBP in gene regulation. (C) 2008 Elsevier GmbH. All rights reserved.