Thyroid Hormone Metabolism Defects in a Mouse Model of SBP2 Deficiency
Thyroid Hormone Metabolism Defects in a Mouse Model of SBP2 Deficiency
复制标题
SBP2 缺陷小鼠模型中的甲状腺激素代谢缺陷
DOI：
10.1210/en.2017-00618
复制
发表时间：
2017-12-01
期刊：
影响因子：
4.8
通讯作者：
Dumitrescu, Alexandra M.
中科院分区：
文献类型：
--
作者：
Fu, Jiao;Fujisawa, Haruki;Dumitrescu, Alexandra M.
硒半胱氨酸插入序列结合蛋白2(SBP2)是硒蛋白合成过程中的一个重要因子。SBP2缺陷患者具有特征性的甲状腺表型，并有其他表现，如生长迟缓、男性不育、运动协调能力受损和发育迟缓。甲状腺表型已经成为这一缺陷的病因学特征，并被认为是碘甲状腺原氨酸脱碘酶硒酶缺陷的原因。为了研究SBP2和硒蛋白在甲状腺生理中的作用并回答人类综合征提出的问题，我们建立了三苯氧胺诱导的Sbp2条件性基因敲除(ICKO)小鼠模型。这些Sbp2基因缺陷小鼠的血清甲状腺激素(T4)、促甲状腺激素和反三碘甲腺原氨酸(T3)水平较高，与人类SBP2缺乏的表型相似，而血清T3水平正常。肝脏T4和T3含量反映血清水平，脱碘酶1表达和酶活性降低。相反，大脑T3含量降低，表明局部甲状腺功能减退，甲状腺激素(TH)正调控基因无毛的表达减少证实了这一点。有趣的是，大脑T4含量与高水平的血清T4水平并不平行，TH转运体的表达减少。大脑中脱碘酶2的活性和脱碘酶3的表达均降低。其他硒蛋白在脑、肝脏和血清中的表达和/或活性降低，从而表明硒蛋白合成的全球缺陷。Sbp2 iCKO小鼠复制了SBP2缺乏症的甲状腺表型，是促进我们了解SBP2在甲状腺动态平衡中的作用以及研究与人类疾病相关的硒蛋白生物学的重要工具。
Selenocysteine insertion sequence binding protein 2 (SBP2) is an essential factor in selenoprotein synthesis. Patients with SBP2 defects have a characteristic thyroid phenotype and additional manifestations such as growth delay, male infertility, impaired motor coordination, and developmental delay. The thyroid phenotype has become pathognomonic for this defect, and putative deficiencies in the iodothyronine deiodinases selenoenzymes have been implicated. To investigate the role of SBP2 and selenoproteins in thyroid physiology and answer questions raised by the human syndrome, we generated a tamoxifen-inducible Sbp2 conditional knockout (iCKO) mouse model. These Sbp2-deficient mice have high serum thyroxine (T4), thyrotropin, and reverse triiodothyronine (T3), similar to the human phenotype of SBP2 deficiency, whereas serum T3 is normal. Their liver T4 and T3 content reflect the serum levels, and deiodinase 1 expression and enzymatic activity were decreased. In contrast, brain T3 content is decreased, indicative of local hypothyroidism, confirmed by the decreased expression of the thyroid hormone (TH) positively regulated gene hairless. Interestingly, the cerebrum T4 content did not parallel the high serum T4 levels, and the expression of TH transporters was decreased. Deiodinase 2 enzymatic activity and deiodinase 3 expression were decreased in cerebrum. The expression and/or activity of other selenoproteins were decreased in brain, liver, and serum, thus demonstrating a global deficiency in selenoprotein synthesis. Sbp2 iCKO mice replicate the thyroid phenotype of SBP2 deficiency and represent an important tool to advance our understanding of the role of SBP2 in thyroid homeostasis and for investigating selenoprotein biology relevant to human disease.