The Thyroid Axis Is Regulated by NCoR1 via Its Actions in the Pituitary.

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Endocrinology (Impact Factor: 4.64). 08/2012; 153(10):5049-57. DOI: 10.1210/en.2012-1504
Source: PubMed

ABSTRACT TSH is the most important biomarker in the interpretation of thyroid function in man. Its levels are determined by circulating thyroid hormone (TH) levels that feed back centrally to regulate the expression of the subunits that comprise TSH from the pituitary. The nuclear corepressor 1 (NCoR1), is a critical coregulator of the TH receptor (TR) isoforms. It has been established to play a major role in the control of TSH secretion, because mice that express a mutant NCoR1 allele (NCoRΔID) that cannot interact with the TR have normal TSH levels despite low circulating TH levels. To determine how NCoR1 controls TSH secretion, we first developed a mouse model that allowed for induction of NCoRΔID expression postnatally to rule out a developmental effect of NCoR1. Expression of NCoRΔID postnatally led to a drop in TH levels without a compensatory rise in TSH production, indicating that NCoR1 acutely controls both TH production and feedback regulation of TSH. To demonstrate that this was a cell autonomous function of NCoR1, we expressed NCoRΔID in the pituitary using a Cre driven by the glycoprotein α-subunit promoter (P-ΔID mice). Importantly, P-ΔID mice have low TH levels with decreased TSH production. Additionally, the rise in TSH during hypothyroidism is blunted in P-ΔID mice. Thus, NCoR1 plays a critical role in TH-mediated regulation of TSH in the pituitary by regulating the repressive function of the TR. Furthermore, these studies suggest that endogenous NCoR1 levels in the pituitary could establish the set point of TSH secretion.

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    ABSTRACT: NCoR1 (Nuclear Receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid Hormone Receptors, NCoR2) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated mice that lacked function of either NCoR1, SMRT or both in the liver only and additionally a global SMRT knock-out model. Despite both corepressors being present in the liver, deletion of SMRT in either euthyroid or hypothyroid animals had little effect on TH signaling. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. Similarly, global disruption of SMRT, unlike the global disruption of NCoR1, did not affect TH levels. While SMRT played little role in TH-regulated pathways, when disrupted in combination with NCoR1 it greatly accentuated the synthesis and storage of hepatic lipid. Taken together these data demonstrate that corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action. However, both corepressors collaborate to control hepatic lipid content, which likely reflects their cooperative activity in regulating the action of multiple NRs including the TH receptor (TR). Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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    ABSTRACT: Thyroid hormone, acting through thyroid hormone receptors is a key regulator of metabolic homeostasis. Repression of transcription is critical component of thyroid hormone signaling and is mediated through the association of corepressor proteins with thyroid hormone receptors. In this review we will discuss recent results elucidating multiple roles for corepressors in mediating thyroid hormones regulation of metabolism.
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Ricardo H Costa-e-Sousa