Additionally, D2 activity was found to be essential to mediate expression of T3-dependent genes in the cerebral cortex, and also necessary to generate the transient cerebral cortex hyperthyroidism present in mice lacking the TH transporter Monocarboxylate transporter 8.
Therefore, sobetirome and Sob-AM2 have the potential to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency.
TRβ protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism.
Consistent upregulation of MCT8 in GD is in line with increased TH release in hyperthyroidism, an assumption supported by our <i>in vitro</i> results showing TSH-dependent upregulation of MCT8.
Regarding the modulation of gene expression in the testis, hypothyroidism increased the expression of Thra1 and decreased the expression of Dio3, and hyperthyroidism increased the expression of Slc16a2.
We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3).
In the presence of an inactive MCT8 transporter, the high blood T3 levels might not be enough to prevent brain damage early in life, while they seem to be able to induce a postnatal state of peripheral hyperthyroidism in other tissues, such as liver, bone and skeletal muscle.