Distinct tissue-specific roles for thyroid hormone receptors β and α1 in regulation of type 1 deiodinase expression

Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T-3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T-3-inducible and here, the regulation of D1 expression by TR alpha1 and TR beta, which act as T-3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TR beta (-/-) but not TR alpha1(-/-) mice. Liver D1 remained weakly T-3 inducible in TR beta (-/-) mice whereas induction was abolished in double mutant TR alpha1(-/-)TR beta (-/-) mice. This indicates that TR beta is primarily responsible for regulating D1 expression whereas TR alpha1 has only a minor role. In kidney, despite the expression of both TR alpha1 and TR beta, regulation relied solely on TR beta, thus revealing a marked tissue restriction in TR isotype utilization. Although TR beta and TR alpha1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TR beta or TR alpha1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TR beta in regulating the thyroid hormone status through D1-mediated metabolism.