| First Author | Matsuo S | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 52 | Pages | 30855-65 |
| PubMed ID | 26527688 | Mgi Jnum | J:227413 |
| Mgi Id | MGI:5700441 | Doi | 10.1074/jbc.M115.694414 |
| Citation | Matsuo S, et al. (2015) Hepatocyte Nuclear Factor 4alpha Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver. J Biol Chem 290(52):30855-65 |
| abstractText | 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 4alpha (HNF4alpha) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4alpha in iron homeostasis was examined using liver-specific HNF4alpha-null mice (Hnf4a(DeltaH) mice). Hnf4a(DeltaH) 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(DeltaH) 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 HNF4alpha-independent manner. HNF4alpha-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4alpha-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4alpha-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4alpha suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4alpha, and hepatic HNF4alpha plays a critical role in iron homeostasis. |
