Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice.
Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice.
复制标题
单羧酸转运蛋白 8 缺乏对小鼠下丘脑-垂体-甲状腺轴的影响。
作者：
M. Trajkovic;Julia Müller;V. Darras;Claudia Groba;Sooyeon Lee;Debra S. Weih;K. Bauer;T. Visser;H. Heuer
在患者中，编码甲状腺激素运输单羧酸转运体8(Mct8)基因的失活突变与严重的精神和神经缺陷以及甲状腺激素水平紊乱有关。后者以高T3和低T4血清浓度为特征在Mct8基因敲除(KO)小鼠中复制，表明MCT8缺乏干扰甲状腺激素的产生和/或代谢。我们对Mct8Ko小鼠的研究确实显示甲状腺T3和T4浓度升高，但没有明显的甲状腺功能亢进的迹象。然而，在TSH刺激下，Mct8 Ko小鼠与野生型小鼠相比，T4降低，T3分泌增加。此外，在Mct8/Trhr1双KO小鼠中也观察到了类似的甲状腺激素分泌模式的变化，其特征是血清T3水平正常，在T4血清浓度很低的情况下肝和肾D1表达正常。这些数据有力地表明，甲状腺中Mct8的缺失通过将分泌的激素的比例向T3移动而影响甲状腺激素的外流。为了验证这一假设，我们培育了Mct8/Pax8双突变小鼠，除了Mct8外，这些小鼠还缺乏功能正常的甲状腺，因此完全是甲状旁腺。在这些动物注射T4或T3后，血清分析显示T3浓度与Pax8Ko小鼠在甲状腺激素替代后观察到的浓度相似，表明Mct8Ko小鼠甲状腺T3分泌增加确实是导致血清T3水平高的重要致病机制。
In patients, inactivating mutations in the gene encoding the thyroid hormone-transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels.
甲状腺激素对促甲状腺素亚基脱辅基蛋白和碳水化合物生物合成的差异调节。
影响因子：
4.8
作者：
Taylor,T;Weintraub,BD
通讯作者：
Weintraub,BD
影响因子：
4.8
作者：
Dumitrescu, Alexandra M.;Liao, Xiao-Hui;Refetoff, Samuel
通讯作者：
Refetoff, Samuel