Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse.
Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse.
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DOI：
10.1210/en.2004-1392
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发表时间：
2005-03
期刊：
影响因子：
4.8
通讯作者：
A. Zavacki;H. Ying;M. Christoffolete;Goele Aerts;Edward C. So;J. Harney;S. Cheng;P. Larsen;
中科院分区：
文献类型：
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作者：
A. Zavacki;H. Ying;M. Christoffolete;Goele Aerts;Edward C. So;J. Harney;S. Cheng;P. Larsen;
具有编码显性失活突变受体 (TR alpha1(PV/+)) 的甲状腺激素受体 (TR) α-1 等位基因的小鼠的血清 T3 水平持续升高（比正常值高 1.9 倍）。它们的肝脏 1 型碘甲状腺原氨酸脱碘酶 (D1) mRNA 和酶活性也显着增加（4 至 5 倍），而其他肝脏 T3 反应基因，如 Spot14 和线粒体 α-甘油磷酸脱氢酶 (α-GPD)，仅为野生型同窝小鼠 (TR α1+/+) 的 0.7 倍和 1.7 倍。为了确定 D1 不成比例升高的原因，TR α1+/+ 和 TR α1(PV/+) 小鼠被致甲状腺功能减退，然后接受 T3 治疗。 TR α1+/+ 和 TR α1(PV/+) 小鼠中，甲状腺功能减退症使肝脏 D1、Spot14 和 α-GPD mRNA 降低至相似水平，而 T3 给药导致 D1 mRNA 升高约 175 倍，但 Spot14 和 α-GPD mRNA 仅增加 3 至 6 倍。有趣的是，在TR α1(PV/+)小鼠中，甲状腺功能减退引起的脑皮质2型碘甲状腺原氨酸脱碘酶活性增加是其3倍，并且这些小鼠没有T3依赖性3型碘甲状腺原氨酸脱碘酶的诱导。因此，相对于其他基因（例如Spot14和α-GPD），肝脏D1对T3的显着反应性解释了TR α1（PV/+）小鼠中血清T3适度增加的相对较大的影响，并且TR α在大脑皮层脱碘酶的T3依赖性正向和负向调节中发挥着关键作用。
Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 iodothyronine deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 iodothyronine deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the deiodinases in the cerebral cortex.