Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice.
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.
Trajkovic-Arsic
Marija
M
Leibniz Institute for Age Research/Fritz Lipmann Institute e.V., Beutenbergstr. 11, D-07745 Jena, Germany.
Müller
Julia
J
Darras
Veerle M
VM
Groba
Claudia
C
Lee
Sooyeon
S
Weih
Debra
D
Bauer
Karl
K
Visser
Theo J
TJ
Heuer
Heike
H
D000818:Animals; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000502:physiology*; D007453:Iodide Peroxidase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics; D027981:Symporters; D013961:Thyroid Gland / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013963:Thyroid Hormones / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D013972:Thyrotropin / Q000494:pharmacology
D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D018025:Receptors, Thyrotropin-Releasing Hormone; C484257:Slc16a2 protein, mouse; D027981:Symporters; D013963:Thyroid Hormones; D013972:Thyrotropin; C109812:iodothyronine deiodinase type I; D007453:Iodide Peroxidase