期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 52, 页码 30855-30865出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.694414
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [25460490]
- Kato Memorial Bioscience Foundation
- Grants-in-Aid for Scientific Research [25460490] Funding Source: KAKEN
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 4 alpha (HNF4 alpha) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4 alpha in iron homeostasis was examined using liver-specific HNF4 alpha-null mice (Hnf4a(Delta H) mice). Hnf4a(Delta H) 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(Delta H) 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 HNF4 alpha-independent manner. HNF4 alpha-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4 alpha-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4 alpha-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4 alpha suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4 alpha, and hepatic HNF4 alpha plays a critical role in iron homeostasis.
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