Impact of Monocarboxylate Transporter-8 Deficiency on the Hypothalamus-Pituitary-Thyroid Axis in Mice

Abstract

In patients, inactivating mutations in the gene encoding the thyroid hormone-transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels.

Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy

“…We suggest that our findings in the thyroidectomised patient could help resolve this issue: since Mct8 is apparently involved in thyroidal hormone secretion (12), it was proposed that unbalanced release of thyroid hormones may underlie the low T 4 levels in the MCT8-deficiency syndrome (13). However, increased instead of decreased T 3 is a robust finding in patients and mice lacking MCT8.…”

“…While T 3 transport is significantly decreased in cortical neurons cultured from Mct8-deficient mice (11), Mct8-deficiency may be partially compensated in some mouse tissues by the coexpression of alternative T 3 transporters (11). Recently, two reports showed the involvement of Mct8 in the secretion of thyroid hormones from the thyroid gland in mice (12,13). However, the paradoxically low total thyroxine (T 4 ) level in the presence of elevated T 3 and normal to high TSH observed both in humans and mice still remains unexplained.…”

Tissue-specific effects of mutations in the thyroid hormone transporter MCT8

“…Thyroidal T4 and T3 content is increased in Mct8 ko vs. wt mice. Furthermore, the increase in serum T4 induced by TSH injection is lower, whereas the increase in serum T3 is higher in Mct8 ko vs. wt mice (18). This suggests that MCT8 plays an important role in T4 secretion by thyroid cells.…”

“…Recent studies have unveiled an important function of MCT8 also in TH secretion (17,18). Thyroidal T4 and T3 content is increased in Mct8 ko vs. wt mice.…”

“…Finally, MCT8 is expressed in both the hypothalamus and the pituitary, and its inactivation may thus interfere with the negative feedback of TH at both sites (12,18). Indeed, serum TSH is usually modestly increased in AHDS patients, which may be compatible with the modestly decreased serum T4 levels but not with the strongly elevated serum T3 levels.…”