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

Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to c ontrol 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 express ion by TR alpha1 and TR beta, which act as T-3-dependent transcription fact ors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TR beta (-/-) but not TR alpha1(-/-) mi ce. Liver D1 remained weakly T-3 inducible in TR beta (-/-) mice whereas in duction was abolished in double mutant TR alpha1(-/-)TR beta (-/-) mice. Th is indicates that TR beta is primarily responsible for regulating D1 expres sion whereas TR alpha1 has only a minor role. In kidney, despite the expres sion of both TR alpha1 and TR beta, regulation relied solely on TR beta, th us revealing a marked tissue restriction in TR isotype utilization. Althoug h TR beta and TR alpha1 mediate similar functions in vitro, these results d emonstrate differential roles in regulating D1 expression in vivo and sugge st that tissue-specific factors and structural distinctions between TR isot ypes contribute to functional specificity. Remarkably, there was an obligat ory 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 i n which the TR sets both basal expression and the spectrum of induced state s. Physiologically, these findings suggest a critical role for TR beta in r egulating the thyroid hormone status through D1-mediated metabolism.