Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism

Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFa secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFa could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload. Overall design: HepG2 mRNA profiles of DMOS, 8HQ, FAC and 8HQ/FAC treated HepG2 cells

肝脏铁过载可诱导肝脏表达铁调素（hepcidin）并调控铁代谢。然而，铁调控铁代谢的机制仍为人所知。细胞内不稳定铁（intracellular labile iron）指未与铁蛋白结合、具有氧化还原活性的短暂性铁离子，是细胞铁代谢的关键交汇节点。目前，细胞内不稳定铁在铁代谢中所发挥的作用已在很大程度上得到阐明。本研究表明，肝细胞内的不稳定铁在铁代谢中具有双重功能：一方面，其可通过内质网应激（ER stress）诱导产生的转录因子，促进肝细胞表达铁调素；另一方面，可通过肝细胞分泌的肿瘤坏死因子α（TNF-α），刺激肝窦内皮细胞（LSECs）的骨形态发生蛋白2（BMP2）与骨形态发生蛋白6（BMP6）表达，进而进一步调控铁代谢。阻断肿瘤坏死因子α可在铁过载状态下扰乱铁代谢稳态。本研究结果揭示了细胞内不稳定铁在铁代谢中的重要作用，同时为铁过载状态下的铁代谢调控提供了全新策略。实验整体设计：对经DMOS、8-羟基喹啉（8HQ）、柠檬酸铁铵（FAC）以及8HQ/FAC联合处理的HepG2细胞进行mRNA表达谱分析。