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 (Hnf4a(ΔH) mice). Hnf4a(ΔH) mice exhibit hypoferremia and a significant change in hepatic gene expression. Notably, the expression of transferrin receptor 2 (Tfr2) mRNA was markedly decreased in Hnf4a(ΔH) 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.
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: the Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizui
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takizawa
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Nagayuki
authors.initials: N
authors.lastname: Ariga
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ozaki
authors.affiliation: the Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan, and.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20852.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: From the Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan, yinoue@gunma-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001665:Binding Sites; D005260:Female; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D007501:Iron
keywords: HNF4α; hepcidin; hypoferremia; iron metabolism; liver; nuclear receptor; transcription regulation; transferrin; transferrin receptor 2