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.
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Two Mct8 KO mouse strains closely recapitulate the thyroid phenotype, but fail to display neurological or behavioral abnormalities.
“two Mct8 knockout (KO) mouse strains closely recapitulate the thyroid phenotype, but they fail to display neurological or behavioral abnormalities (Dumitrescu et al., 2006; Trajkovic et al., 2007).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Dumitrescu et al., 2006
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- Authors
- Dumitrescu, A. M., Liao, X.-H., Weiss, R. E., Millen, K., & Refetoff, S.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Refetoff, Samuel
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2006-09-01
- Volume
- 147
- Issue
- 9
- Pages
- 4036-4043
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2102611661
- Cited by
- 318
- References
- 30
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 3 · 2022: 19 · 2021: 15 · 2020: 11 · 2019: 20 · 2018: 9 · 2017: 21 · 2016: 18 · 2015: 24 · 2014: 23 · 2013: 19 · 2012: 17
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Chicago
- National Institutes of Health (DK 15070)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 15070, DK 58281, DK 20595, R01DK058281)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Chemical Analysis and Environmental Impact
- Keywords
- MCT8, thyroid hormone excess, deiodinase 2, T3, thyroxine, reverse T3, TSH suppression, liver, cerebrum, serum cholesterol, alkaline phosphatase, knockout mice
- MeSH terms
- Alkaline Phosphatase, Animals, Brain Chemistry, Cholesterol, Disease Models, Animal, Drug Resistance, Female, Humans, Hypothalamus, Kinetics, Liver, Male, Mice, Inbred C57BL, Mutation, Phenotype, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine, Mice, Knockout, Membrane Transport Proteins, Monocarboxylic Acid Transporters, Symporters, Mice
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