Triac regulation of transcription is T(3) receptor isoform- and response element-specific

3,5,3'-triiodothyroacetic acid (Triac) is a naturally occurring triiodothyronine (T(3)) analog, which has been used on an empirical basis to treat the syndrome of resistance to thyroid hormone (RTH). The aim of our studies was to compare the effects of Triac and T(3) on negative and positive thyroid hormone response elements (TREs). We used transient transfections with luciferase reporter genes to show that on palindromic, inverted palindrome and human TRH reporters, Triac is more potent than T(3) for transcriptional regulation by TRbeta1 and TRbeta2 isoforms, while regulation by TRalpha1 is equivalent for both ligands. Other TREs (direct repeat, hTSHalpha and hTSHbeta) are not regulated differently by Triac and T(3). Dose-response curves show that the difference between Triac and T(3) is maximal in the 1-10 nM range. Receptor-binding studies reveal a greater affinity of Triac than T(3) for TRbeta1 and TRbeta2 isoforms, which could explain its isoform-specific effects. These data suggest that the TRE- and TR isoform-specific effects of Triac favor its use in RTH.