Iron sensing and regulatory mechanisms of the liver in health and disease

The liver is the central organ for systemic iron metabolism, storing iron and producing the iron regulatory hormone, hepcidin. Hepcidin synthesis is regulated by endothelial cell-hepatocyte interaction via the bone morphogenic protein (BMP)/BMP receptor/hemojuvelin/SMAD pathways. Hepatocellular iron uptake from the circulation is mediated by transferrin receptor 1, for transferrin-bound iron, and Zip14, for non-on transferrin bound iron respectively. Within the cytosol, iron is shuttled by poly-r(C) binding proteins (PCBP) and is stored as ferritin. Regarding intracellular iron metabolism, iron responsive element (IRE)-iron responsive protein (IRP) interaction is essential for post-transcriptional regulation. In addition, iron-related proteins are transcriptionally regulated by hypoxia-inducible factor (HIF) and nuclear factor kappa B (NF-кB), depending on both iron and reactive oxygen species (ROS). In hepatic diseases, including hepatocellular carcinoma (HCC), these regulatory mechanisms are dysregulated.