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.

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…Upon bindingofT 3 ,TRsgainaffinityforcoactivatorsandtriggerT 3 -dependent gene transcription. Thus, the role of T 3 is not only to promote expression of T 3 -dependent genes but also to relieve TR-mediated gene repression (44). The present observation that fasting shuts down DIO2 expression (and T 3 production) via shifting the balance between PI3K-mTORC2-Akt and FOXO1 highlights the importance of unoccupied TRs.…”

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

“…TRα1 and TRβ1 are the two main thyroid hormone-binding isoforms and regulate transcription either by direct binding to thyroid hormone response elements (TREs) in target genes or by modulating the activity of other transcription factors and signaling pathways (21,22). TRβ mediates the majority of the actions of T3 in the liver (23), playing an important role in regulating metabolism (24,25), regeneration (26), senescence (27), and carcinogenesis (28).…”

Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological implications

“…THs play important roles in many biological processes, including modulation of growth, differentiation of many organs, energy homeostasis, and numerous key metabolic pathways (Brent, 2012). The THs, including triiodothyronine (T3) and thyroxine (T4), are produced by the thyroid gland and transported in human plasma by primarily binding to two proteins, transthyretin (TTR) and thyroxine-binding globulin (TBG), responsible for 20% and 75% binding activity, respectively.…”