Mechanisms of thyroid hormone action
Gregory A. Brent
Gregory A. Brent
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(9):3035-3043. https://doi.org/10.1172/JCI60047.
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Science in Medicine

Mechanisms of thyroid hormone action

Abstract

Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform–specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.

Authors

Gregory A. Brent

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Figure 1

Nuclear action of thyroid hormone.

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Nuclear action of thyroid hormone. Shown are the key components required...
Shown are the key components required for thyroid hormone action, as demonstrated by a range of clinical observations. (A) The TR gene has 2 major isoforms, TRβ and TRα; the structures of TRα1 and TRα2 (non–T3-binding) and TRβ1 and TRβ2 are shown. (B) The major thyroid hormone forms, T4, T3, and rT3. (C) Circulating T4 is converted locally in some tissues by membrane-bound D2 to the active form, T3. D3 converts T3 to the inactive rT3. (D) In specific tissues, such as brain, transporters such as MCT8 transport T4 and T3 into the cell. Unliganded TR heterodimerizes with RXR and binds to a TRE and then to a corepressor, such as NCoR or SMRT, repressing gene expression. T3 binding to the ligand-binding domain results in movement of the carboxyterminal helix 12, disruption of corepressor binding, and promotion of coactivator binding, which then leads to recruitment of polymerase III and initiation of gene transcription.