Thyroid hormone receptor α and regulation of type 3 deiodinase.

Mice deficient in thyroid hormone receptor alpha (TRalpha) 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. TRalpha 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 TRalphaKO mice. We observed that T(3) treatment increased D3 mRNA in mouse embryonic fibroblasts obtained from WT or TRbetaKO mice, but not in those from TRalphaKO 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 hTRalpha but not with hTRbeta. Moreover, treatment of GH3 cells with T(3) increased D3 mRNA after overexpression of TRalpha. The region necessary for the T(3)-TRalpha stimulation of the hD3 promoter (region -1200 to -1369) was identified by transfection studies in Neuro2A cells that stably overexpress either TRalpha or TRbeta. These results indicate that TRalpha mediates the up-regulation of D3 by TH in vitro. TRalphaKO 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 TRalpha results in decreased clearance of TH by D3 and contributes to the TH hypersensitivity