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

Research output: Contribution to journalArticle

14 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

Fingerprint

Hepatocyte Nuclear Factor 4
Transferrin Receptors
Metabolism
Liver
Iron
GC Rich Sequence
Genes
Transcription Initiation Site
Gene expression
Homeostasis
Binding Sites
Mouse Trfr2 protein
Gene Expression
Biological systems
Small Interfering RNA
Transcriptional Activation
Toxicity
Reactive Oxygen Species

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Matsuo, S., Ogawa, M., Muckenthaler, M. U., Mizui, Y., Sasaki, S., Fujimura, T., ... 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

Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver. / Matsuo, Shunsuke; Ogawa, Masayuki; Muckenthaler, Martina U.; Mizui, Yumiko; Sasaki, Shota; Fujimura, Takafumi; Takizawa, Masayuki; Ariga, Nagayuki; Ozaki, Hiroaki; Sakaguchi, Masakiyo; Gonzalez, Frank J.; Inoue, Yusuke.

In: Journal of Biological Chemistry, Vol. 290, No. 52, 25.12.2015, p. 30855-30865.

Research output: Contribution to journalArticle

Matsuo, S, Ogawa, M, Muckenthaler, MU, Mizui, Y, Sasaki, S, Fujimura, T, Takizawa, M, Ariga, N, Ozaki, H, Sakaguchi, M, Gonzalez, FJ & Inoue, Y 2015, 'Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver', Journal of Biological Chemistry, vol. 290, no. 52, pp. 30855-30865. https://doi.org/10.1074/jbc.M115.694414
Matsuo, Shunsuke ; Ogawa, Masayuki ; Muckenthaler, Martina U. ; Mizui, Yumiko ; Sasaki, Shota ; Fujimura, Takafumi ; Takizawa, Masayuki ; Ariga, Nagayuki ; Ozaki, Hiroaki ; Sakaguchi, Masakiyo ; Gonzalez, Frank J. ; Inoue, Yusuke. / Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 52. pp. 30855-30865.
@article{4ac44e2d20cd43469e14f9e15a44a970,
title = "Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver",
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.",
author = "Shunsuke Matsuo and Masayuki Ogawa and Muckenthaler, {Martina U.} and Yumiko Mizui and Shota Sasaki and Takafumi Fujimura and Masayuki Takizawa and Nagayuki Ariga and Hiroaki Ozaki and Masakiyo Sakaguchi and Gonzalez, {Frank J.} and Yusuke Inoue",
year = "2015",
month = "12",
day = "25",
doi = "10.1074/jbc.M115.694414",
language = "English",
volume = "290",
pages = "30855--30865",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "52",

}

TY - JOUR

T1 - Hepatocyte nuclear factor 4α controls iron metabolism and regulates transferrin receptor 2 in mouse liver

AU - Matsuo, Shunsuke

AU - Ogawa, Masayuki

AU - Muckenthaler, Martina U.

AU - Mizui, Yumiko

AU - Sasaki, Shota

AU - Fujimura, Takafumi

AU - Takizawa, Masayuki

AU - Ariga, Nagayuki

AU - Ozaki, Hiroaki

AU - Sakaguchi, Masakiyo

AU - Gonzalez, Frank J.

AU - Inoue, Yusuke

PY - 2015/12/25

Y1 - 2015/12/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84951843454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951843454&partnerID=8YFLogxK

U2 - 10.1074/jbc.M115.694414

DO - 10.1074/jbc.M115.694414

M3 - Article

C2 - 26527688

AN - SCOPUS:84951843454

VL - 290

SP - 30855

EP - 30865

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 52

ER -