Thyroid Hormone Receptor α and Regulation of Type 3 Deiodinase

Mice deficient in thyroid hormone receptor alpha (TR alpha) display hypersensitivity to thyroid hormone (TH), with normal serum TSH but diminished serum T-4. Our aim was to determine whether altered TH metabolism played a role in this hypersensitivity. TR alpha knockout (KO) mice have lower levels of rT(3), and lower rT(3)/T-4 ratios compared with wild-type (WT) mice. These alterations could be due to increased type 1 deiodinase (D1) or decreased type 3 deiodinase (D3). No differences in D1 mRNA expression and enzymatic activity were found between WT and TR alpha KO mice. We observed that T-3 treatment increased D3 mRNA in mouse embryonic fibroblasts obtained from WT or TR beta KO mice, but not in those from TR alpha KO mice. T-3 stimulated the promoter activity of 1.5 kb 5'-flanking region of the human (h) DIO3 promoter in GH3 cells after cotransfection with hTR alpha but not with hTR beta. Moreover, treatment of GH3 cells with T3 increased D3 mRNA after overexpression of TR alpha. The region necessary for the T3-TR alpha stimulation of the hD3 promoter (region -1200 to -1369) was identified by transfection studies in Neuro2A cells that stably overexpress either TR alpha or TR beta. These results indicate that TR alpha mediates the up-regulation of D3 by TH in vitro. TR alpha KO mice display impairment in the regulation of D3 by TH in both brain and pituitary and have reduced clearance rate of TH as a consequence of D3 deregulation. We conclude that the absence of TR alpha results in decreased clearance of TH by D3 and contributes to the TH hypersensitivity. (Molecular Endocrinology 25:575-583, 2011)