Open AccessHepatocyte Nuclear Factor 4α Contributes to Thyroid Hormone Homeostasis by Cooperatively Regulating the Type 1 Iodothyronine Deiodinase Gene with GATA4 and Krüppel-Like Transcription Factor 9
Author(s) -
Hiroto Ohguchi,
Toshiya Tanaka,
Aoi Uchida,
Kenta Magoori,
Hiromi Kudo,
Insook Kim,
Kenji Daigo,
Iori Sakakibara,
Masashi Okamura,
Hideo Harigae,
Takeshi Sasaki,
Timothy F. Osborne,
Frank J. Gonzalez,
Takao Hamakubo,
Tatsuhiko Kodama,
Juro Sakai
Publication year - 2008
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.02154-07
Subject(s) - transactivation , hepatocyte nuclear factor 4 , iodothyronine deiodinase , biology , thyroid hormone receptor , endocrinology , transcription factor , hepatocyte nuclear factors , medicine , gata4 , thyroid hormone receptor beta , deiodinase , zinc finger transcription factor , nuclear receptor , thyroid , microbiology and biotechnology , zinc finger , triiodothyronine , hormone receptor , gene , genetics , cancer , breast cancer
Type 1 iodothyronine deiodinase (Dio1), a selenoenzyme catalyzing the bioactivation of thyroid hormone, is highly expressed in the liver. Dio1 mRNA and enzyme activity levels are markedly reduced in the livers of hepatocyte nuclear factor 4α (HNF4α)-null mice, thus accounting for its liver-specific expression. Consistent with this deficiency, serum T4 and rT3 concentrations are elevated in these mice compared with those in HNF4α-floxed control littermates; however, serum T3 levels are unchanged. Promoter analysis of the mouseDio1 gene demonstrated that HNF4α plays a key role in the transactivation of the mouseDio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4α site (direct repeat 1 [TGGACAAAGGTGC]; HNF4α-RE) is crucial for transactivation of the mouseDio1 gene by HNF4α. Mouse Dio1 is also stimulated by thyroid hormone signaling, but a direct role for thyroid hormone receptor action has not been reported. We also showed that thyroid hormone-inducible Krüppel-like factor 9 (KLF9) stimulates the mouseDio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4α-RE. Furthermore, KLF9 functions together with HNF4α and GATA4 to synergistically activate the mouseDio1 promoter, suggesting that Dio1 is regulated by thyroid hormone in the mouse through an indirect mechanism requiring prior KLF9 induction. In addition, we showed that physical interactions between the C-terminal zinc finger domain (Cf) of GATA4 and activation function 2 of HNF4α and between the basic domain adjacent to Cf of GATA4 and a C-terminal domain of KLF9 are both required for this synergistic response. Taken together, these results suggest that HNF4α regulates thyroid hormone homeostasis through transcriptional regulation of the mouseDio1 gene with GATA4 and KLF9.