Gao Junwei, Chen Juxing, Kramer Maxwell, Tsukamoto Hidekazu, Zhang An-Sheng, Enns Caroline A
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
Cell Metab. 2009 Mar;9(3):217-27. doi: 10.1016/j.cmet.2009.01.010.
The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein HFE. They have lower levels of hepcidin than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the alpha3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE alpha3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf.
机体用以感知铁水平以维持铁稳态的机制尚不清楚。最常见的遗传性铁过载患者，其遗传性血色素沉着症蛋白HFE存在突变。他们的铁调素水平低于未受影响的个体。铁调素是一种肝脏肽类激素，对铁从肠道向血液的外排起负调节作用。我们报告了两种肝细胞系，即转染了HFE的WIF-B细胞和HepG2细胞，其中铁调素表达对铁负载的转铁蛋白有反应。当内源性转铁蛋白受体2（TfR2）被抑制时，或者在缺乏功能性TfR2或HFE的原代肝细胞中，这种反应消失。此外，用仅含α3和胞质结构域的HFE嵌合体转染的转铁蛋白处理的HepG2细胞，可上调铁调素表达。由于HFE的α3结构域与TfR2相互作用，这些结果支持了我们的发现，即TfR2/HFE复合物是全转铁蛋白对铁调素进行转录调控所必需的。
