This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: MCB.02154-07v1 28/12/3917    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Ohguchi, H. Articles by Sakai, J. PubMed PubMed Citation Articles by Ohguchi, H. Articles by Sakai, J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2008, p. 3917-3931, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02154-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hepatocyte Nuclear Factor 4 Contributes to Thyroid Hormone Homeostasis by Cooperatively Regulating the Type 1 Iodothyronine Deiodinase Gene with GATA4 and Krüppel-Like Transcription Factor 9 ^,

Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan,¹ Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan,² Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,³ Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92717-3900⁴

Received 4 December 2007/ Returned for modification 15 January 2008/ Accepted 5 April 2008

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 4 (HNF4)-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 HNF4-floxed control littermates; however, serum T₃ levels are unchanged. Promoter analysis of the mouse Dio1 gene demonstrated that HNF4 plays a key role in the transactivation of the mouse Dio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4 site (direct repeat 1 [TGGACAAAGGTGC]; HNF4-RE) is crucial for transactivation of the mouse Dio1 gene by HNF4. 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 mouse Dio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4-RE. Furthermore, KLF9 functions together with HNF4 and GATA4 to synergistically activate the mouse Dio1 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 HNF4 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 HNF4 regulates thyroid hormone homeostasis through transcriptional regulation of the mouse Dio1 gene with GATA4 and KLF9.

Published ahead of print on 21 April 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.