Choi Si-On, Cho Young-Suk, Kim Hye-Lim, Park Jong-Wan
Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
Biochem Biophys Res Commun. 2007 Apr 27;356(1):312-7. doi: 10.1016/j.bbrc.2007.02.137. Epub 2007 Mar 5.
Hepcidin, a liver peptide, systemically inhibits iron utilization and is downregulated under hypoxic conditions. However, little is known about the mechanism underlying the hypoxic suppression of hepcidin. Here, we tested the possibility that HIF-1 and ROS are involved in hepcidin regulation. Hepcidin mRNA, pre-mRNA, and protein levels were reduced in mouse livers and in HepG2 cells after hypoxic incubation, and HIF-1 overexpression and knock-down studies showed that hepcidin regulation is independent of HIF-1. On the other hand, ROS levels were significantly elevated in hypoxic HepG2 cells, and anti-oxidants prevented the hypoxic down-regulation of hepcidin. Conversely, a prooxidant, H(2)O(2), suppressed hepcidin expression in these cells even in normoxia. Of the various transcription factors examined, C/EBPalpha and STAT-3 were found to dissociate from hepcidin promoter under hypoxia, but to become fully engaged after anti-oxidant treatment. These results suggest that ROS repress the hepcidin gene by preventing C/EBPalpha and STAT-3 binding to hepcidin promoter during hypoxia.
铁调素是一种肝脏肽，可系统性抑制铁的利用，且在缺氧条件下表达下调。然而，关于缺氧抑制铁调素的潜在机制知之甚少。在此，我们测试了缺氧诱导因子-1（HIF-1）和活性氧（ROS）参与铁调素调节的可能性。缺氧孵育后，小鼠肝脏和肝癌细胞系HepG2中的铁调素信使核糖核酸（mRNA）、前体mRNA和蛋白质水平均降低，而过表达和敲低HIF-1的研究表明，铁调素的调节独立于HIF-1。另一方面，缺氧的HepG2细胞中ROS水平显著升高，抗氧化剂可防止铁调素的缺氧下调。相反，即使在常氧条件下，促氧化剂过氧化氢（H₂O₂）也会抑制这些细胞中铁调素的表达。在所检测的各种转录因子中，发现缺氧时CCAAT增强子结合蛋白α（C/EBPα）和信号转导子与转录激活子3（STAT-3）与铁调素启动子解离，但抗氧化剂处理后则完全结合。这些结果表明，缺氧时ROS通过阻止C/EBPα和STAT-3与铁调素启动子结合来抑制铁调素基因。
