Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver

Shunsuke Matsuo, Masayuki Ogawa, Martina U. Muckenthaler, Yumiko Mizui, Shota Sasaki, Takafumi Fujimura, Masayuki Takizawa, Nagayuki Ariga, Hiroaki Ozaki, Masakiyo Sakaguchi, Frank J. Gonzalez, Yusuke Inoue

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15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)30855-30865
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number52
DOIs
Publication statusPublished - Dec 25 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Matsuo, S., Ogawa, M., Muckenthaler, M. U., Mizui, Y., Sasaki, S., Fujimura, T., Takizawa, M., Ariga, N., Ozaki, H., Sakaguchi, M., Gonzalez, F. J., & Inoue, Y. (2015). Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver. Journal of Biological Chemistry, 290(52), 30855-30865. https://doi.org/10.1074/jbc.M115.694414