Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor α
Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor α
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DOI：
10.1073/pnas.011306998
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发表时间：
2001-01-02
影响因子：
11.1
通讯作者：
Refetoff, S
中科院分区：
文献类型：
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作者：
Macchia, PE;Takeuchi, Y;Refetoff, S
甲状腺激素受体（TR）的四种亚型中只有三种，α 1，β 1。和β 2结合甲状腺激素（TH），被认为是真正的TR，TR α 2结合DNA上的TH反应元件，但其在体内的作用仍然未知。我们生产了TR α完全缺陷（TR α（o/o））的小鼠，尽管血清甲状腺素（T-4）较低，但仍保持正常的血清促甲状腺激素（TSH）浓度，这表明对TH的敏感性增加。因此，我们检查了TH（L-3，3 '，5-三碘甲状腺原氨酸，L-T-3）给予TH剥夺和完整TR α（o/o）小鼠的影响。对照是相同品系的野生型（WT）小鼠和由于TR β（TR β（-/-））缺陷而对TH具有抗性的小鼠。在肝脏中，与WT小鼠相比，T-3在TR α（o/o）中产生显著更大的反应，在TR β（-/-）中产生较小的反应。相比之下，TR α（o/o）小鼠对L-T-3的心脏反应不存在或降低，而WT和TR β（-/-）小鼠对L-T-3的心脏反应相似，支持TR α 1是心脏中主要的TH依赖性TR亚型的观点。5-给予完整小鼠三碘甲腺原氨酸（L-T-3）比WT小鼠对TR α（o/o）中血清T-4产生更大的抑制，并使TSH对TSH释放激素的反应减少更大。这是体内证明TR缺陷可以增强对TH的敏感性，这种作用可能是由于在表达TR β同种型的组织中TR α 2的组成型“沉默”作用的消除，
Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1. and beta2, bind thyroid hormone (TH) and are considered to be true TRs, TR alpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TR alpha (TR alpha (o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T-4), suggesting increased sensitivity to TH, We therefore examined the effects of TH (L-3,3',5-triiodothyronine, L-T-3) given to TH-deprived and to intact TR alpha (o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TR beta (TR beta (-/-)). In liver, T-3 produced significantly greater responses in TR alpha (o/o) and smaller responses in TR beta (-/-) as compared with WT mice. In contrast, cardiac responses to L-T-3 were absent or reduced in TR alpha (o/o), whereas they were similar in WT and TR beta (-/-) mice, supporting the notion that TR alpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T-3) given to intact mice produced a greater suppression of serum T-4 in TR alpha (o/o) than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH, This effect is likely due to the abrogation of the constitutive "silencing" effect of TR alpha2 in tissues expressing the TR beta isoforms,