Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver
Iron is an essential element in biological systems, but excess iron promotes the formation of reactive oxygen species, resulting in cellular toxicity. Several iron-related genes are highly expressed in the liver, a tissue in which hepatocyte nuclear factor 4α (HNF4α) plays a critical role in control...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
November 2, 2015
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| In: |
JBC papers in press
Year: 2015, Volume: 290, Issue: 52, Pages: 30855-30865 |
| DOI: | 10.1074/jbc.M115.694414 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1074/jbc.M115.694414 Verlag, lizenzpflichtig, Volltext: http://www.jbc.org/content/290/52/30855 
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| Author Notes: | Shunsuke Matsuo, Masayuki Ogawa, Martina U. Muckenthaler, Yumiko Mizui, Shota Sasaki, Takafumi Fujimura, Masayuki Takizawa, Nagayuki Ariga, Hiroaki Ozaki, Masakiyo Sakaguchi, Frank J. Gonzalez, and Yusuke Inoue |
| Summary: | Iron is an essential element in biological systems, but excess iron promotes the formation of reactive oxygen species, resulting in cellular toxicity. Several iron-related genes are highly expressed in the liver, a tissue in which hepatocyte nuclear factor 4α (HNF4α) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4α in iron homeostasis was examined using liver-specific HNF4α-null mice (Hnf4aΔH mice). Hnf4aΔH mice exhibit hypoferremia and a significant change in hepatic gene expression. Notably, the expression of transferrin receptor 2 (Tfr2) mRNA was markedly decreased in Hnf4aΔH mice. Promoter analysis of the Tfr2 gene showed that the basal promoter was located at a GC-rich region upstream of the transcription start site, a region that can be transactivated in an HNF4α-independent manner. HNF4α-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4α-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4α-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4α suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4α, and hepatic HNF4α plays a critical role in iron homeostasis. |
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| Item Description: | Gesehen am 09.06.2020 |
| Physical Description: | Online Resource |
| DOI: | 10.1074/jbc.M115.694414 |