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

Background and aimsLiver iron loading can induce hepatic expression of hepcidin and regulate iron metabolism. However, the mechanism by which hepatocyte senses iron loading and further regulates iron metabolism remains unclear. Intracellular labile iron is nonferritin-bound and redox active; it is transitory, and it serves as a crossroads of cellular iron metabolism, the effect of intracellular labile iron in iron metabolism regulation is particularly poorly understood. MethodsAn intracellular labile iron overload cell model was established using ferric ammonium citrate (FAC) and the lipophilic iron chelator 8-hydroxyquinoline (8HQ/FAC). RNA-Seq was performed to screen the genes that were highly expressed exclusively in 8HQ/FAC-treated HepG2 cells. High-iron-diet mice model and Hfe knockout hemochromatosis mice were used to investigate the importance of tumor necrosis factor alpha (TNF alpha) in iron metabolism. ResultsIntracellular labile iron in hepatocytes had a dual function in iron metabolism: It induced hepatocytes to express hepcidin via endoplasmic reticulum stress-induced transcription factors, and it stimulated expression of bone morphogenic protein 6 (BMP6, regulator of iron metabolism) in liver sinusoidal endothelial cells (LSECs) via promoting the secretion of TNF alpha by the hepatocytes. Blockade of TNF alpha dysregulated iron metabolism during iron overload. Furthermore, administration of TNF alpha could reduce iron burden in Hfe knockout hemochromatosis mice. ConclusionsOur findings reveal the importance of intracellular labile iron in iron metabolism, and propose that TNF alpha might be a novel therapeutic target for HFE-associated hemochromatosis. [GRAPHICS] .