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. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler played a significant role in advancing our understanding of the function of hepcidin. This review is dedicated to his memory.
This review is dedicated to the memory of Dr. Ernest Beutler who had a career-long interest in iron homeostasis and its relationship to erythropoiesis. Guided by his legendary knowledge of all aspects of hematology and careful analysis of experimental and clinical data, he contributed much to modern hematology and was not afraid to challenge established beliefs. Even after he fell terminally ill, he continued to make major contributions to the study of iron regulation. His ideas, attitudes, and achievements inspired us all.
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.
Hepcidin is encoded as an 84-aa prepropeptide, containing an N-terminal 24-aa endoplasmic reticulum-targeting signal sequence. The 60-aa prohormone contains a consensus furin cleavage motif, and several proprotein convertases were reported to process hepcidin in vitro including furin, PACE4, PC5/6 and PC7/LPC. The processing step occurs in the Golgi apparatus, does not appear to be regulated, and only the mature peptide, but not the prohepcidin, was shown to be secreted from cells.
The mature hormone circulates in plasma and its binding to α2-macroglobulin has been reported. While this interaction was shown to promote hepcidin activity in vitro, the effect on hepcidin clearance is still unknown. A major route of hepcidin clearance is renal excretion. When kidney function is normal, urinary hepcidin concentrations correlate well with circulating hepcidin levels, with no apparent regulation of the excretion process. However, based on the comparison between serum and urinary concentrations, it appears that only 5% of hepcidin from plasma filtered in the kidneys ends up intact in the urine, suggesting that hepcidin may not be freely filtered in the glomerulus and/or that filtered hepcidin is reabsorbed and degraded in proximal tubules similarly to other small peptide hormones. Hepcidin may also be cleared by receptor-mediated endocytosis in tissues expressing its receptor ferroportin, as indicated by the accumulation of radiolabeled hepcidin in ferroportin-rich tissues and the degradation of the endocytosed ferroportin-hepcidin complex in cultured cells. How much hepcidin catabolism occurs by renal clearance or by degradation in target tissues remains to be determined.