Distinct modulatory roles for thyroid hormone receptors TRα and TRβ 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 (T3) receptor (TR)α and TRβ bind this motif thereby modulating SREBP1-dependent activation of ABCD2. Unliganded TRβ, but not TRα, represses ABCD2 induction independently of DNA binding. However, activation by TRα and derepression of TRβ are T3-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 T3 and TRα levels) but downregulated in adults (with low T3 and TRα but elevated TRβ levels). This temporal repression of Abcd2 is blunted in TRβ-deficient mice, and the response to manipulated T3 states is abrogated in TRα-deficient mice. These findings show that TRα and TRβ 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.