Tissue-Specific Thyroid Hormone Deprivation and Excess in Monocarboxylate Transporter (Mct) 8-Deficient Mice

Abstract

Mutations of the X-linked thyroid hormone (TH) transporter (monocarboxylate transporter, MCT8) produce in humans unusual abnormalities of thyroid function characterized by high serum T3 and low T4 and rT3. The mechanism of these changes remains obscure and raises questions regarding the regulation of intracellular availability and metabolism of TH. To study the pathophysiology of MCT8 deficiency, we generated Mct8 knockout mice. Male mice deficient in Mct8 (Mct8(-/y)) replicate the thyroid abnormalities observed in affected men. TH deprivation and replacement with L-T3 showed that suppression of TSH required higher serum levels T3 in Mct8(-/y) than wild-type (WT) littermates, indicating hypothalamus and/or thyrotroph resistance to T3. Furthermore, T4 is required to maintain the high serum T3 level because the latter was not different between the two genotypes during administration of T3. Mct8(-/y) mice have 2.3-fold higher T3 content in liver associated with 6.1- and 3.1-fold increase in deiodinase 1 mRNA and enzymatic activity, respectively. The relative T3 excess in liver of Mct8(-/y) mice produced a decrease in serum cholesterol (79 +/- 18 vs. 137 +/- 38 mg/dl in WT) and an increase in alkaline phosphatase (107 +/- 23 vs. 58 +/- 3 U/liter in WT) levels. In contrast, T3 content in cerebrum was 1.8-fold lower in Mct8(-/y) mice, associated with a 1.6- and 10.6-fold increase in D2 mRNA and enzymatic activity, respectively, as previously observed in TH-deprived WT mice. We conclude that cell-specific differences in intracellular TH content due to differences in contribution of the various TH transporters are responsible for the unusual clinical presentation of this defect, in contrast to TH deficiency.

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…Increased choline and myoinositol levels and decreased N-acetyl aspartate detected by MRspectroscopy were associated with the degree of dysmyelination found on MRI [100]. [18,101] replicate the characteristic thyroid tests abnormalities found in humans and, in this respect, have been invaluable in understanding the mechanisms responsible for the thyroid phenotype [102]. The variable availability of the circulating hormone to tissues, depending on the redundant presence of TH cell membrane transporters was demonstrated by measurement of tissue T 3 .…”

“…This paradox is observed clinically and in biochemical tests some of which suggest TH deficiency and others sufficiency or excess, depending on the level of TRβ gene expression in various tissues [17]. The syndrome of TH cell membrane transport defect (THCMTD) presents a similar paradox, as subjects have high serum T 3 concentration but the uptake of TH is not uniform in all tissues and cell types [18].…”

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

“…Mct8 ko have been generated to study the pathogenic mechanism of AHDS, but disappointingly these mice do not show any obvious neurological phenotype (12,15). However, they do show the same changes in serum TH levels as AHDS patients, including a markedly decreased serum T4 and a markedly increased serum T3.…”

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

“…Expression of MCT8 in the mouse brain (9) supported the idea that TH import into neurons may be affected in patients afflicted with the Allan-Herndon-Dudley syndrome. Mice deficient in MCT8 recapitulate the disturbed serum thyroid hormone parameters (10,11) but exhibit only mild neurological abnormalities (12). Murine neurons are apparently protected from the lack of MCT8 by expression of alternative T 3 transporters such as Lat2, which is not present in human developing neurons (12).…”