The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis
The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis
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DOI：
10.1210/me.2010-0462
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发表时间：
2011-02-01
影响因子：
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通讯作者：
Hollenberg, Anthony N.
中科院分区：
文献类型：
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作者：
Astapova, Inna;Vella, Kristen R.;Hollenberg, Anthony N.
核受体辅阻遏物（NCoR）在甲状腺激素（TH）作用中的作用一直难以辨别，因为NCoR的整体缺失是胚胎致死的。为了避免这一点，我们开发了一种小鼠，这种小鼠全局表达一种修饰的NCoR蛋白（NCoR Delta ID），这种蛋白不能被甲状腺激素受体（TR）招募。这些小鼠存在低血清T-4和T-3浓度，伴有正常TSH水平，提示中枢性甲状腺功能减退。然而，它们正常生长，并且在多个组织中具有增加的能量消耗和正常或升高的TR靶基因表达，这与甲状腺功能减退不一致。虽然这些研究结果意味着增加外周敏感性TH，下丘脑-垂体-甲状腺轴是不是更敏感的TH浓度的急性变化，但似乎是复位识别TH水平降低为正常。此外，甲状腺本身虽然大小正常，但非甲状腺球蛋白结合的T-4和T-3水平降低，对TSH的反应性降低。因此，TR-NCoR相互作用控制全身TH敏感性以及下丘脑-垂体-甲状腺轴所有水平的设定点。这些结果表明，NCoR水平可以改变细胞特异性TH的行动，不会反映的血清TSH。（分子内分泌学25：212-224，2011）
The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoR Delta ID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T-4 and T-3 concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T-4 and T-3 and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH. (Molecular Endocrinology 25: 212-224, 2011)