Hepcidin - an iron controlling hormone

Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation, it controls the export of iron from duodenal epithelial cells, hepatocytes and macrophages and consequently influences the level of serum iron available for the bone marrow and other tissues heavily dependent on iron supply (R1)

Hepcidin in Iron overload and iron deficiency

Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. (R2)

Liver origin

The hormone hepcidin, a 25-amino-acid (aa) peptide, is the principal regulator of iron absorption and its distribution to tissues. Hepcidin is synthesized predominantly in hepatocytes, but its low levels of expression in other cells and tissues, including macrophages, adipocytes and brain, may also be important for the autocrine and paracrine control of iron fluxes at the local level. (R2)

Intestinal Iron Uptake

The phenotypes of hepcidin excess and deficiency indicate that hepcidin inhibits intestinal iron uptake and the release of iron from macrophages recycling old red blood cells. When hepcidin was overexpressed during embryonic development, fetuses developed severe iron deficiency anemia and most died at birth indicating that hepcidin also inhibited the placental transport of iron. Hepcidin also appears to block, at least partially, the export of stored iron from hepatocytes as indicated by hepatic iron accumulation in mice carrying hepcidin-overproducing tumors. (R2)

Hepcidin reduces amount of ferroportin

Posttranslational control of ferroportin levels by its ligand hepcidin is the major mode of ferroportin regulation. The binding of hepcidin to ferroportin triggers the internalization and degradation of the receptor-ligand complex. The binding likely involves disulfide exchange between one of disulfide bonds of hepcidin and the exofacial ferroportin thiol residue Cys326. Patients with C326S mutations develop early-onset iron overload, and the mutant ferroportin lost its ability to bind hepcidin in vitro. Once internalized, the hepcidin-ferroportin complex is degraded in lysosomes and cellular iron export ceases. (R2)

Ferroportin is the only known cellular iron exporter in vertebrates. Hence diminished amount of that receptor-exporter leads to iron overload inside the cell (hepatocytes).

Regulation of Hepcidin

Hepcidin is homeostatically regulated by iron and erythropoietic activity. Iron excess stimulates hepcidin production, and increased concentrations of the hormone in turn block dietary iron absorption thus preventing further iron loading. Conversely, hepcidin is suppressed in iron deficiency, allowing increased absorption of dietary iron and replenishment of iron stores. Increased erythropoietic activity also suppresses hepcidin production. (R2)

Hepcidin is also increased in inflammation and infection, and it is presumed that this regulation evolved as a host defense strategy to limit iron availability to microorganisms. (R2)

Vitamin C inhibits hepcidin

Oral vitamin C therapy resulted in a statistically significant reduction in both hepcidin and hs-CRP levels in the study group after 3 months. (R3)

Vitamin C directly inhibits hepcidin expression within HepG2 cells. (R4)

Exercising increases Hepcidin

This search found that a single session of endurance exercise (intervallic or continuous) at moderate or vigorous intensity (60–90% VO2peak) stimulates an increase in the circulating levels of hepcidin between 0 h and 6 h after the end of the exercise bout, peaking at ~3 h post-exercise. (R5)