Bárez-López Soledad, Obregon Maria Jesus, Martínez-de-Mena Raquel, Bernal Juan, Guadaño-Ferraz Ana, Morte Beatriz
1 Department of Endocrine and Nervous System Pathophysiology, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain .
2 Department of Endocrine, U-708, Center for Biomedical Research on Rare Diseases (Ciberer) , Instituto de Salud Carlos III, Madrid, Spain .
Thyroid. 2016 May;26(5):618-26. doi: 10.1089/thy.2015.0388. Epub 2016 Feb 3.
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. Mutations in the MCT8 gene lead to profound psychomotor retardation and abnormal thyroid hormone serum levels with low thyroxine (T4) and high triiodothyronine (T3). Currently, therapeutic options for patients are limited. Triiodothyroacetic acid (TRIAC) has potential therapeutic value. The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO).
Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g of body weight/day, given in drinking water, from postnatal day 21 to 30. TRIAC, T4 and T3 levels in plasma, as well as T3 and TRIAC content in the cerebral cortex and striatum were measured by specific radioimmunoassays. The activities of deiodinases 1 and 2 were measured in liver and cortex. The effect of TRIAC treatment in the expression of T3-dependent genes was measured in the heart, cerebral cortex, and striatum.
Plasma TRIAC concentration were the same in Wt and Mct8KO animals after treatment. TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO mice. Deiodinase 1 activity and gene expression in the liver increased, while it did not have any effect on the expression of Serca2a in the heart. TRIAC treatment did not induce the expression of T3-dependent genes in the cerebral cortex or striatum, but further decreased expression of Flywch2 in the cortex and Aldh1a1 and Flywch2 in the striatum. Direct measurements of TRIAC and T3 content in the cortex and striatum revealed a decrease in T3 after treatment with no significant increase in the level of endogenous TRIAC.
Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels. TRIAC has a direct effect on deiodinase 1 in the liver and does not have an effect on gene expression in the heart. The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.
单羧酸转运体8（MCT8）是一种甲状腺激素特异性细胞膜转运体。MCT8基因突变会导致严重的精神运动发育迟缓以及甲状腺激素血清水平异常，表现为低甲状腺素（T4）和高三碘甲状腺原氨酸（T3）。目前，针对此类患者的治疗选择有限。三碘甲状腺乙酸（TRIAC）具有潜在的治疗价值。本研究旨在评估治疗剂量的TRIAC对Mct8基因敲除小鼠（Mct8KO）的影响及疗效。
从出生后第21天至30天，野生型（Wt）和Mct8KO小鼠通过饮用含30 ng TRIAC/g体重/天的水进行治疗。采用特异性放射免疫分析法测定血浆中的TRIAC、T4和T3水平，以及大脑皮层和纹状体中的T3和TRIAC含量。测定肝脏和皮层中脱碘酶1和2的活性。在心脏、大脑皮层和纹状体中检测TRIAC治疗对T3依赖性基因表达的影响。
治疗后，Wt和Mct8KO动物的血浆TRIAC浓度相同。TRIAC治疗显著降低了Wt和Mct8KO小鼠的血浆T4水平，并使Mct8KO小鼠的T3水平降至正常。肝脏中脱碘酶1的活性和基因表达增加，而对心脏中Serca2a的表达没有影响。TRIAC治疗未诱导大脑皮层或纹状体中T3依赖性基因的表达，但进一步降低了皮层中Flywch2以及纹状体中Aldh1a1和Flywch2的表达。对大脑皮层和纹状体中TRIAC和T3含量的直接测量显示，治疗后T3降低，内源性TRIAC水平无显著升高。
治疗剂量的TRIAC可使Mct8KO小鼠的血浆T3水平恢复正常，但严重降低了T4水平。TRIAC对肝脏中的脱碘酶1有直接作用，对心脏中的基因表达无影响。治疗后血浆TRIAC水平的升高不足以增加大脑中的TRIAC水平并促进脑细胞中T3依赖性基因的表达。相反，它导致了大脑甲状腺功能减退状态，T3含量降低。
