Distinct modulatory roles for thyroid hormone receptors TRalpha and TRbeta in SREBP1-activated ABCD2 expression

Area of Science:

• Molecular Endocrinology
• Gene Regulation
• Peroxisomal Disorders

Background:

• ABCD2 encodes a peroxisomal ABC transporter with functional overlap with X-linked adrenoleukodystrophy protein.
• Pharmacological induction of ABCD2 is a potential therapeutic strategy for adrenoleukodystrophy.
• Sterol regulatory element-binding proteins (SREBPs) regulate ABCD2 expression via SRE/DR-4 elements.

Purpose of the Study:

• To investigate the role of thyroid hormone receptors (TRalpha and TRbeta) in modulating SREBP1-dependent ABCD2 gene activation.
• To elucidate the mechanism of TR-SREBP interaction at the SRE/DR-4 motif.
• To understand the in vivo regulation of Abcd2 expression by TR isoforms and thyroid hormone.

Main Methods:

• Electrophoretic mobility shift assays (EMSA) to assess TR and SREBP1 interaction.
• Analysis of Abcd2 expression in liver tissues of wild-type, TRbeta-deficient, and TRalpha-deficient mice.
• Studies involving manipulated thyroid hormone (T(3)) states in mice.

Main Results:

• TRalpha and TRbeta bind to the SRE/DR-4 motif, modulating SREBP1-activated ABCD2 expression.
• Unliganded TRbeta represses ABCD2 induction, while TRalpha activation and TRbeta derepression are T(3)-dependent.
• TR isoforms directly interact with SREBP1 at the SRE/DR-4 element, as supported by EMSA.
• Temporal regulation of Abcd2 expression in mice correlates with TRalpha and TRbeta levels and T(3) status.
• TRbeta deficiency alters temporal Abcd2 repression, and TRalpha deficiency affects T(3)-mediated responses.

Conclusions:

• TRalpha and TRbeta differentially regulate SREBP1-activated ABCD2 expression through distinct mechanisms at overlapping SRE/DR-4 elements.
• Thyroid hormone receptors and SREBPs exhibit a novel cross-talk in gene regulation.
• These findings provide insights into the complex regulation of ABCD2 and potential therapeutic targets for adrenoleukodystrophy.