Monocarboxylate transporter-8 （MCT8） is a specific thyroid hormone transporter, essential for the uptake of thyroid hormone into target tissues. Mutations in the MCT8 gene have been identified as the cause of Allan-...Monocarboxylate transporter-8 （MCT8） is a specific thyroid hormone transporter, essential for the uptake of thyroid hormone into target tissues. Mutations in the MCT8 gene have been identified as the cause of Allan-Herndon-Dudley syndrome （AHDS）. It has been reported that soy isoflavones influence thyroid hormone system and can interact with thyroid hormone transporter proteins. Therefore, the present study aimed to find out whether soy isoflavones （genistein, daidzein and glycitein） can be used as a natural inhibitor to target MCT8 in AHDS. Docking studies were performed for soy isoflavones in order to evaluate their binding affinity to MCT8 protein using AutoDock4 （version 4.2.6） and AutoDock Vina. After docking, the ligands were ranked according to their binding energy and the best lead compound was selected based on the least binding energy. The docking results indicated that daidzein possesses the lowest binding energy against MCT8. Moreover, it was found that the residues PRO-338, HIS-341, and GLU-348 were involved in hydrogen bond interactions with genistein and daidzein. This study suggests that daidzein is a promising natural inhibitor to target MCT8 in AHDS.展开更多
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gen e of which is located on the X chromosome. We tested whether mutations in MCT8 c ause severe psychomotor retardation and high serum triiod...Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gen e of which is located on the X chromosome. We tested whether mutations in MCT8 c ause severe psychomotor retardation and high serum triiodothyronine (T3) concent rations in five unrelated young boys. The coding sequence of MCT8 was analysed b y PCR and direct sequencing of its six exons. In two patients,gene deletions of 2·4 kb and 24 kb were recorded and in three patients missense mutations Ala150 Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X linked psychomotor retardation is due to a defect in T3 entry i nto neurons through MCT8, resulting in impaired T3 action and metabolism.展开更多
Background Iodine deficiency is a major factor affecting thyroid auto-regulation,the quantity of iodine may greatly influence the synthesis of thyroid hormones （THs）.It has long been believed that TH enters the cell...Background Iodine deficiency is a major factor affecting thyroid auto-regulation,the quantity of iodine may greatly influence the synthesis of thyroid hormones （THs）.It has long been believed that TH enters the cell through passive diffusion.Recent studies have suggested that several transporters could facilitate transportation of TH.The monocarboxylate transporter 8 （MCT8） was identified as a very active and specific TH transporter.The purpose of this study was to investigate whether iodine insufficient affected the expression of MCT8 in the thyroid gland.Methods Sixty BALB/c mice were randomly divided into two groups：control group was fed with standard feed （iodine concentration of 300 μg/kg）; while low-iodine （LI） group received iodine-insufficient feed （iodine concentration of 20-40 μg/kg）.After 3 months,10 mice of each group were sacrificed.The remaining 20 mice of each group were kept till 6 months.From the LI group,we randomly selected 15 mice and injected triiodothyronine （T3,100 μg/kg body weight per day） intraperitoneally for 24,48 or 72 hours （5 mice for each time-point）.Then,all the mice were sacrificed.Mouse serum thyroxine （T4）,T3,and thyroid-stimulating hormone （TSH） levels were determined by chemiluminescence immunoassay （CIA）.The protein content or messenger RNA （mRNA） level of thyroid MCT8 was measured by Western blotting analysis or real time RT-PCR respectively.MCT8 subcellular location in thyroid tissues was probed with immunohistochemistry （IHC） assay.Results We found that mouse serum T3 and T4 levels decreased and TSH level increased by the end of the third month.Consistent with these findings,there was significant goiter and hypothyroidism in the LI group.Meanwhile,the MCT8 mRNA increased to 1.36-fold of the level in the control group at the 3rd month.At 6th month,the serum T4 level in LI mice remained at a lower level,and MCT8 mRNA expression continued rising to nearly 1.60-fold compared with the control group.The protein content was also about 3 times higher than that in the control group.IHC results also revealed MCT8 was of higher expression and localized in the cytoplasm of thyroid follicular cells.After providing exogenous T3 to iodine deficient mice,the serum T3 and T4 gradually increased,whereas MCT8 mRNA and protein both started to decrease and returned to the same level as the control group.Conclusion There is a compensatory increase in thyroid MCT8 expression to enhance its capability to transport TH from thyroid to the blood circulation in iodine deficient mice.展开更多
文摘Monocarboxylate transporter-8 （MCT8） is a specific thyroid hormone transporter, essential for the uptake of thyroid hormone into target tissues. Mutations in the MCT8 gene have been identified as the cause of Allan-Herndon-Dudley syndrome （AHDS）. It has been reported that soy isoflavones influence thyroid hormone system and can interact with thyroid hormone transporter proteins. Therefore, the present study aimed to find out whether soy isoflavones （genistein, daidzein and glycitein） can be used as a natural inhibitor to target MCT8 in AHDS. Docking studies were performed for soy isoflavones in order to evaluate their binding affinity to MCT8 protein using AutoDock4 （version 4.2.6） and AutoDock Vina. After docking, the ligands were ranked according to their binding energy and the best lead compound was selected based on the least binding energy. The docking results indicated that daidzein possesses the lowest binding energy against MCT8. Moreover, it was found that the residues PRO-338, HIS-341, and GLU-348 were involved in hydrogen bond interactions with genistein and daidzein. This study suggests that daidzein is a promising natural inhibitor to target MCT8 in AHDS.
文摘Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gen e of which is located on the X chromosome. We tested whether mutations in MCT8 c ause severe psychomotor retardation and high serum triiodothyronine (T3) concent rations in five unrelated young boys. The coding sequence of MCT8 was analysed b y PCR and direct sequencing of its six exons. In two patients,gene deletions of 2·4 kb and 24 kb were recorded and in three patients missense mutations Ala150 Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X linked psychomotor retardation is due to a defect in T3 entry i nto neurons through MCT8, resulting in impaired T3 action and metabolism.
基金This work was supported by two grants from the National Nature Science Foundation of China （No. 30901460 and No. 30972559）.
文摘Background Iodine deficiency is a major factor affecting thyroid auto-regulation,the quantity of iodine may greatly influence the synthesis of thyroid hormones （THs）.It has long been believed that TH enters the cell through passive diffusion.Recent studies have suggested that several transporters could facilitate transportation of TH.The monocarboxylate transporter 8 （MCT8） was identified as a very active and specific TH transporter.The purpose of this study was to investigate whether iodine insufficient affected the expression of MCT8 in the thyroid gland.Methods Sixty BALB/c mice were randomly divided into two groups：control group was fed with standard feed （iodine concentration of 300 μg/kg）; while low-iodine （LI） group received iodine-insufficient feed （iodine concentration of 20-40 μg/kg）.After 3 months,10 mice of each group were sacrificed.The remaining 20 mice of each group were kept till 6 months.From the LI group,we randomly selected 15 mice and injected triiodothyronine （T3,100 μg/kg body weight per day） intraperitoneally for 24,48 or 72 hours （5 mice for each time-point）.Then,all the mice were sacrificed.Mouse serum thyroxine （T4）,T3,and thyroid-stimulating hormone （TSH） levels were determined by chemiluminescence immunoassay （CIA）.The protein content or messenger RNA （mRNA） level of thyroid MCT8 was measured by Western blotting analysis or real time RT-PCR respectively.MCT8 subcellular location in thyroid tissues was probed with immunohistochemistry （IHC） assay.Results We found that mouse serum T3 and T4 levels decreased and TSH level increased by the end of the third month.Consistent with these findings,there was significant goiter and hypothyroidism in the LI group.Meanwhile,the MCT8 mRNA increased to 1.36-fold of the level in the control group at the 3rd month.At 6th month,the serum T4 level in LI mice remained at a lower level,and MCT8 mRNA expression continued rising to nearly 1.60-fold compared with the control group.The protein content was also about 3 times higher than that in the control group.IHC results also revealed MCT8 was of higher expression and localized in the cytoplasm of thyroid follicular cells.After providing exogenous T3 to iodine deficient mice,the serum T3 and T4 gradually increased,whereas MCT8 mRNA and protein both started to decrease and returned to the same level as the control group.Conclusion There is a compensatory increase in thyroid MCT8 expression to enhance its capability to transport TH from thyroid to the blood circulation in iodine deficient mice.
