Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine
Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine
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DOI：
10.1172/jci77588
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发表时间：
2015-02-01
影响因子：
15.9
通讯作者：
Bianco, Antonio C.
中科院分区：
文献类型：
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作者：
de Castro, Joao Pedro Werneck;Fonseca, Tatiana L.;Bianco, Antonio C.
目前对甲状腺功能减退患者的治疗方法是左旋甲状腺素(L-T4)，同时使血清促甲状腺激素(TSH)正常化。然而，用L-T4单药治疗使血清TSH正常化后，血清3，5，3‘-三碘甲状腺原氨酸(T3)相对较低，而血清甲状腺激素/T3(T4/T3)比值较高。在下丘脑-垂体二分体以及大脑的其余部分，存在的13个中的大部分是由T4通过2型脱碘酶(D2)局部脱碘产生的；这一途径受到泛素连接酶WSB-1泛素化D2的自我限制。在这里，我们确定D2泛素化的组织特异性差异解释了长期皮下植入L-T4微丸的成年甲状腺切除(TX)大鼠T4/T3血清高比率的原因。虽然L-T4降低了全身D2依赖性T4向T3的转化，但下丘脑D2活性仅受L-T4的轻微影响。对携带星形胶质细胞特异性Wsb1缺失的小鼠进行的体内研究以及不同组织提取物驱动的D2泛素化的体外分析表明，下丘脑的D2泛素化相对较少。因此，与其他表达D2的组织相比，下丘脑对T4的敏感度增加。这些研究揭示了D2泛素化的组织特异性差异是TRH/TSH反馈机制的固有特性，并表明只有持续给予L-T4和L-T3才能使TX大鼠的T3依赖代谢标志物和基因表达谱完全正常化。
The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroidstimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3'-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of 13 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.