Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action

We propose that specificity of interaction among thyroid hormone receptor subtypes with particular cofactors may influence whether there is stimulation or inhibition of mRNA expression

Peter M. Sadow; Olivier Chassande; Karine Gauthier; Jacques Samarut; Jianming Xu; Bert W. O′Malley; Roy E. Weiss

2015

Scholarcy highlights

  • Isoforms of the thyroid hormone receptorα and TRβ genes mediate thyroid hormone action
  • TRβ−/− mice had a markedly reduced response, a reduction further compounded by deficiency in both TRβ and steroid receptor coactivator-1). These studies investigate the in vivo effect of TR subtypes in peripheral tissues, by focusing on animal growth, heart rates, EE, and markers of TH action in the liver and heart
  • SRC-1−/− mice achieve adult linear and body weights that are not different from those of WT animals, loss of SRC-1 in combination with either TR subtype results in linear and weight growth retardation compared with WT at both 5 wk and 9 wk
  • We did not investigate expression of growth hormone in TR subtype/SRC-1-deficient mice, we speculate that these levels may be normal, as has been shown in TRα0/0, TRα1−/− and TRβ−/−, and SRC-1−/− mice
  • The use of a TRβ isoform-specific ligand, GC-1, failed to maintain core body temperature and reduced stimulation of uncoupling protein in brown adipose tissue of hypothyroid mice. These data indicate that TRα mediates the increased EE observed in response to TH, supporting previous observations, and that SRC-1 is not necessary for this action of TH
  • At week 5, lengths of TRβ−/− and TRα0/0 mice were 14% less than those of WT mice and remained from 5 to 10% less compared with WT mice at week 9
  • We conclude that 1) in the absence of TRα or TRβ, SRC-1 is important for normal growth; 2) SRC-1 partially mediates the TH effect on heart rate by TRα and TRβ; 3) we have identified two new TH-responsive markers in the liver mediated by TRβ: osteopontin and glutathione S-transferase; and 4) we have shown that SRC-1 may mediate the hypersensitivity to TH seen in TRα0/0 mice, as demonstrated by 5′deoiodinase expression in liver

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