Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (Mct) 8-deficient mice
Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (Mct) 8-deficient mice
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DOI：
10.1210/en.2006-0390
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发表时间：
2006-09-01
期刊：
影响因子：
4.8
通讯作者：
Refetoff, Samuel
中科院分区：
文献类型：
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作者：
Dumitrescu, Alexandra M.;Liao, Xiao-Hui;Refetoff, Samuel
X连锁甲状腺激素(TH)转运体(单羧酸转运体，MCT8)的突变会在人类中产生异常的甲状腺功能异常，其特征是血清T-3升高，T-4和RT(3)降低。这些变化的机制仍然不清楚，并提出了关于细胞内TH的可用性和新陈代谢的调节的问题。为了研究MCT8缺陷的病理生理学，我们产生了Mct8基因敲除小鼠。Mct8基因缺陷的雄性小鼠(Mct8(-/y))复制了在受影响男性中观察到的甲状腺异常。Th缺乏和用L-T-3替代表明，抑制TSH需要Mct8(-/y)比野生型(WT)产仔更高的血清T-3水平，这表明下丘脑和/或促甲状腺激素对T-3具有抵抗力。此外，T-4需要维持较高的血清T-3水平，因为在服用T-3期间，两种基因型的T-3水平没有差异。Mct8(-/y)小鼠的肝脏T-3含量增加了2.3倍，脱碘酶1mRNA和酶活性分别增加了6.1和3.1倍。Mct8(-/y)小鼠肝脏中相对过量的T3导致血清胆固醇降低(WT为79+/-18比137+/-38 mg/dl)，碱性磷酸酶水平升高(WT为107+/-23比58+/-3U/L)。相比之下，Mct8(-/y)小鼠大脑中的T-3含量降低了1.8倍，与之前在缺乏TH的WT小鼠中观察到的D2mRNA和酶活性分别增加了1.6倍和10.6倍相关。我们得出结论，由于不同的TH转运体的贡献不同，细胞内TH含量的特异性差异是导致这种缺陷的不寻常临床表现的原因，而不是TH缺陷。
Mutations of the X-linked thyroid hormone (TH) transporter (monocarboxylate transporter, MCT8) produce in humans unusual abnormalities of thyroid function characterized by high serum T-3 and low T-4 and rT(3). The mechanism of these changes remains obscure and raises questions regarding the regulation of intracellular availability and metabolism of TH. To study the pathophysiology of MCT8 deficiency, we generated Mct8 knockout mice. Male mice deficient in Mct8 (Mct8(-/y)) replicate the thyroid abnormalities observed in affected men. TH deprivation and replacement with L-T-3 showed that suppression of TSH required higher serum levels T-3 in Mct8(-/y) than wild-type (WT) littermates, indicating hypothalamus and/or thyrotroph resistance to T-3. Furthermore, T-4 is required to maintain the high serum T-3 level because the latter was not different between the two genotypes during administration of T-3. Mct8(-/y) mice have 2.3-fold higher T-3 content in liver associated with 6.1- and 3.1-fold increase in deiodinase 1 mRNA and enzymatic activity, respectively. The relative T3 excess in liver of Mct8(-/y) mice produced a decrease in serum cholesterol (79 +/- 18 vs. 137 +/- 38 mg/dl in WT) and an increase in alkaline phosphatase (107 +/- 23 vs. 58 +/- 3 U/liter in WT) levels. In contrast, T-3 content in cerebrum was 1.8-fold lower in Mct8(-/y) mice, associated with a 1.6- and 10.6-fold increase in D2 mRNA and enzymatic activity, respectively, as previously observed in TH-deprived WT mice. We conclude that cell-specific differences in intracellular TH content due to differences in contribution of the various TH transporters are responsible for the unusual clinical presentation of this defect, in contrast to TH deficiency.