Distinct roles of deiodinases on the phenotype of Mct8 defect: A comparison of eight different mouse genotypes

Xiao Hui Liao, Caterina Di Cosmo, Alexandra M. Dumitrescu, Arturo Hernandez, Jacqueline Van Sande, Donald L. St. Germain, Roy E. Weiss, Valerie Anne Galton, Samuel Refetoff

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Mice deficient in the thyroid hormone (TH) transporter Mct8 (Mct8KO) have increased 5′-deiodination and impaired TH secretion and excretion. These and other unknown mechanisms result in the low-serum T4, high T 3, and low rT3 levels characteristic of Mct8 defects. We investigated to what extent each of the 5′-deiodinases (D1, D2) contributes to the serum TH abnormalities of the Mct8KO by generating mice with all combinations of Mct8 and D1 and/or D2 deficiencies and comparing the resulting eight genotypes. Adding D1 deficiency to that of Mct8 corrected the serum TH abnormalities of Mct8KO mice, normalized brain T3 content, and reduced the impaired expression of TH-responsive genes. In contrast, Mct8D2KO mice maintained the serum TH abnormalities of Mct8KO mice. However, the serum TSH level increased 27-fold, suggesting a severely impaired hypothalamo-pituitary-thyroid axis. The brain of Mct8D2KO manifested a pattern of more severe impairment of TH action than Mct8KO alone. In triple Mct8D1D2KO mice, the markedly increased serum TH levels produced milder brain defect than that of Mct8D2KO at the expense of more severe liver thyrotoxicosis. Additionally, we observed that mice deficient in D2 had an unexplained marked reduction in the thyroid growth response to TSH. Our studies on these eight genotypes provide a unique insight into the complex interplay of the deiodinases in the Mct8 defect and suggest that D1 contributes to the increased serum T3 in Mct8 deficiency, whereas D2 mainly functions locally, converting T4 to T3 to compensate for distinct cellular TH depletion in Mct8KO mice.

Original languageEnglish (US)
Pages (from-to)1180-1191
Number of pages12
JournalEndocrinology
Volume152
Issue number3
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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    Liao, X. H., Di Cosmo, C., Dumitrescu, A. M., Hernandez, A., Van Sande, J., St. Germain, D. L., Weiss, R. E., Galton, V. A., & Refetoff, S. (2011). Distinct roles of deiodinases on the phenotype of Mct8 defect: A comparison of eight different mouse genotypes. Endocrinology, 152(3), 1180-1191. https://doi.org/10.1210/en.2010-0900