title: Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes.
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 T(4), high T(3), and low rT(3) 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 T(3) 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 T(3) in Mct8 deficiency, whereas D2 mainly functions locally, converting T(4) to T(3) to compensate for distinct cellular TH depletion in Mct8KO mice.
authors.affiliation: Department of Medicine, The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Caterina
authors.initials: C
authors.lastname: Di Cosmo
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Dumitrescu
authors.forename: Arturo
authors.initials: A
authors.lastname: Hernandez
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Van Sande
authors.forename: Donald L
authors.initials: DL
authors.lastname: St Germain
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
authors.forename: Valerie Anne
authors.initials: VA
authors.lastname: Galton
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005838:Genotype; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D027501:Monocarboxylic Acid Transporters; D027981:Symporters
chemical_list: D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C484257:Slc16a2 protein, mouse; D027981:Symporters; D007453:Iodide Peroxidase