The use of mice deficient in MCT8 to identify a mechanism regulating thyroid hormone secretion

The mechanism of thyroid hormone (TH) secretion from the thyroid gland into the bloodstream is still unknown. The aim of my thesis has been to investigate the role of monocarboxylate transporter 8 (MCT8) in this process. To accomplish the goal, we used the Mct8 deficient mice (Mct8KO), generated by homologous recombination. MCT8 is a specific transporter of TH across the cell membrane, active in both uptake and efflux. Mutations of MCT8 gene cause in human severe psychomotor retardation and thyroid function test abnormalities. The Mct8KO mice faithfully replicate the endocrine aberrances observed in humans, including a low concentration of serum thyroxine (T4). This latter finding cannot be fully explained by increased deiodination. Here, we have shown that Mct8 is localized at the basolateral membrane of thyrocytes and that the serum TH concentration is reduced in Mct8KO mice early after being taken off a treatment that almost completely depleted the thyroid gland of TH. Furthermore, thyroid glands in Mct8KO mice contained 2.3-fold and 1.5-fold more non thyroglobulin associated T4 and triiodothyronine (T3), respectively, than did those in wild-type (Wt) mice. This was independent of deiodination, as comparable increases were also found in Mct8KO mice which lacked the types 1 and 2 deiodinases. In addition, depletion of thyroidal TH content was slower during iodine deficiency. After administration of 125I, the rate of both its secretion from the thyroid gland and its appearance in the serum as trichloroacetic acid-precipitable radioactivity were greatly reduced in Mct8KO mice. Similarly, the secretion of T4 induced by injection of thyrotropin was reduced in Mct8KO in which endogenous TSH and T4 were suppressed by administration of T3. This study is the first to demonstrate that Mct8 is involved in the secretion of TH from the thyroid gland. The defect in the efflux contributes, in part, to the low serum T4 level observed in Mct8 deficiency.