User:Kf7tgy22/Hepcidin/Bibliography

Regulation
Hepcidin synthesis and secretion by the liver is controlled by iron stores, inflammation (hepcidin is an acute phase reactant), hypoxia, and erythropoiesis. In response to large iron stores, production of Bone Morphogenic Protein (BMP) is induced, which binds to receptors on hepatocytes and induces hepcidin expression via the SMAD pathway. Inflammation causes an increase in hepcidin production by releasing the signaling molecule interleukin-6 (IL-6), which binds to a receptor and upregulates the HAMP gene via the JAK/STAT pathway. Hypoxia negatively regulates hepcidin production via production the transcription factor hypoxia-inducible factor (HIF), which under normal conditions is degraded by von Hippel-Lindau (VHL) and prolyl dehydrogenase (PHD). When hypoxia is induced, however, PHD is inactivated, thus allowing HIF to down-regulate hepcidin production. Erythropoiesis decreases hepcidin production via production of erythropoietin (EPO), which has been shown to down-regulate hepcidin production.

Severe anemia is associated with low hepcidin levels, even in the presence of inflammation. Erythroferrone, produced in erythroblasts, has been identified as inhibiting hepcidin and so providing more iron for hemoglobin synthesis in situations such as stress erythropoiesis.

Vitamin D has been shown to decrease hepcidin, in cell models looking at transcription and when given in large doses to human volunteers. Optimal function of hepcidin may be predicated upon the adequate presence of vitamin D in the blood.

Function
Hepcidin is a regulator of iron metabolism. It inhibits iron transport by binding to the iron export channel ferroportin which is located in the basolateral plasma membrane of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages), ultimately resulting in ferroportin breakdown in lysosomes. It has been shown that Hepcidin is able to bind to the central cavity of Ferroportin, thus occluding iron export from the cell. This suggests that Hepcidin is able to regulate iron export independently of Ferroportin endocytosis and ubiquitination, and is thus quickly inducible and reversible. In enterocytes, this prevents iron transmission into the hepatic portal system, thereby reducing dietary iron absorption. In macrophages, ferroportin inhibition causes iron sequestration within the cell. Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation, such as kidney failure and that may explain why patient with end stage renal failure may not respond to oral Iron replacement.

Any one of several mutations in hepcidin result in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin. Mutations in TMPRSS6 can cause anemia through dysregulation of Hepcidin.

Hepcidin has strong antimicrobial activity against Escherichia coli strain ML35P and Neisseria cinerea and weaker antimicrobial activity against Staphylococcus epidermidis, Staphylococcus aureus and Streptococcus agalactiae. It is also active against the fungus Candida albicans, but has no activity against Pseudomonas aeruginosa.