Endocrine Abstracts

Thyroid hormone plays an important role in the development of tissues, in particular the brain, and in the regulation of their metabolic activity throughout life. Most of the actions of thyroid hormone are initiated by binding of T3 to its nuclear receptor, resulting in an altered transcription of thyroid hormone-responsive genes. Also the metabolism of thyroid hormone by the deiodinases D1, D2 and D3 takes place intracellularly. D2 and D3 are important for local regulation of bioactive T3 in the brain. D2 is located mostly in astrocytes and converts the prohormone T4 to T3; D3 is mostly located in neurons, the primary target cell for T3 in brain, and catalyzes the degradation of T4 to rT3 and of T3 to 3,3′-T2.

Both metabolism and action of thyroid hormone require the transport of iodothyronines across the cell membrane. This does not occur as previously thought by simple diffusion but is mediated by transport proteins. Several transporters have been identified to be capable of transporting iodothyronines, including Na-taurocholate cotransporting polypeptide (NTCP), different members of the organic anion transporting polypeptide (OATP) family, the L-type amino transporters LAT1 and LAT2, and the “monocarboxylate transporters” MCT8 and MCT10.

Among these transporters OATP1C1 and MCT8 are importantly expressed in brain. OATP1C1 is located predominantly in brain capillaries and shows specificity for T4 and rT3 over T3 as the ligand. It is thought to be immportant for transport of T4 across the blood-brain barrier. MCT8 is expressed especially in neurons and also extensively in the choroid plexus. It is thought to be essential for T3 uptake in neurons.

The gene coding for MCT8 is located on the X chromosome. Its physiological relevance has been indicated by studies in male patients with severe psychomotor retardation and abnormal serum thyroid hormone levels, in particular a markedly elevated serum T3. All patients with this Allan-Herndon-Dudley syndrome have been identifed with different mutations in the MCT8 gene, resulting in a major defect in T3 transport. This reduced cellular T3 uptake represents a novel mechanism of thyroid hormone resistance. The neurological phenotype of the patients is explained by the lack of T3 supply to central neurons during brain development. The increase in serum T3 is less readily explained and appears to involve among other things a decreased T3 clearance by brain D3 and an increased expression of hepatic and renal D1.