Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism. 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 TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα 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中铁调素（hepcidin）的表达，并调控铁代谢。然而，铁调控铁代谢的具体机制仍有待阐明。细胞内不稳定铁（intracellular labile iron）指未结合铁蛋白、具有氧化还原活性的短暂性铁池，是细胞铁代谢的关键交汇点。此前关于细胞内不稳定铁在铁代谢中所发挥的作用已基本得到阐明。本研究表明，肝细胞内的不稳定铁在铁代谢中发挥双重功能：一方面，其可通过内质网应激（ER stress）诱导的转录因子，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（TNFα），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TNFα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的干预思路。
实验设计：对分别经DMOS、8HQ、FAC及8HQ/FAC处理的HepG2细胞进行mRNA表达谱分析。