TY - JOUR
T1 - Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (Mct) 8-deficient mice
AU - Dumitrescu, Alexandra M.
AU - Liao, Xiao Hui
AU - Weiss, Roy E.
AU - Millen, Kathleen
AU - Refetoff, Samuel
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006
Y1 - 2006
N2 - 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 rT 3. 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, T 4 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.
AB - 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 rT 3. 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, T 4 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.
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U2 - 10.1210/en.2006-0390
DO - 10.1210/en.2006-0390
M3 - Article
C2 - 16709608
AN - SCOPUS:33747590148
VL - 147
SP - 4036
EP - 4043
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 9
ER -