Serum iron levels are determined both by intestinal absorption and macrophage recycling of iron from hemoglobin because there is no efficient MAPK Inhibitor Library pathway for iron excretion.[10] Regulatory effectors that modulate intestinal iron absorption probably also modulate the release of iron from tissue macrophages and hepatocytes. Hepcidin appears to be such a regulatory effector. It is a small, cysteine-rich peptide, cleaved from a larger precursor.[11-13] Hepcidin, which was originally isolated from human serum and urine as a peptide with antimicrobial activity,[11,

13] is a hormone exclusively synthesized in the liver and a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages.[12, 14] Increased plasma iron from macrophage recycling of aged red blood cells or from intestinal absorption of iron stimulates hepatocytes through several signaling pathways to produce more hepcidin. Ferroportin is an iron exporter on the surface of absorptive intestinal enterocytes, macrophages, hepatocytes, and placental cells, all of which release iron into plasma.[15-17] Circulating hepcidin can Doxorubicin in vitro bind to ferroportin, cause internalization, and trap iron

in hepatocytes, macrophages, and absorptive enterocytes.[18] Thus, coupling the internalization of ferroportin to hepcidin levels generates a homeostatic loop regulating the iron plasma level and the tissue distribution of iron. 上海皓元 Knowledge of how hepcidin transcription is regulated within hepatocytes appears to be indispensable for understanding the mechanisms underlying hepatic iron overload in chronic hepatitis

C because hepcidin is the central regulator of systemic iron homeostasis. Important elements of the signaling pathway present on the hepatic plasma membrane that affect hepcidin transcription include transferrin receptor 2 (TfR2),[19] HFE,[20] which is the protein affected in the most common form of genetic hemochromatosis, and hemojuverin (HJV),[21] a member of the bone morphogenetic protein (BMP) receptor family. The mechanisms by which TfR2, HFE, and HJV are linked to changes in hepcidin transcription are incompletely understood, but the discovery of HJV revealed that the well-known sons of mothers against decapentaplegic (SMAD) signal transduction pathway was important in this process.[22] Notably, animals that lack hepatocyte SMAD4, a protein that combines with other members of the SMAD family to regulate transcription of target genes, develop significant iron overload associated with a profound reduction in hepcidin expression.[23] Interleukin 6 (IL-6) activates hepcidin transcription through a pathway that involves janus kinase-signal transducer and activator of transcription (STAT) signaling and a binding site for the transcription factor STAT3.