Iron regulation by hepcidin

Abstract

Discovery and function of hepcidin in iron homeostasisHepcidin is a key peptide hormone that regulates iron homeostasis in chordates. Hepcidin was initially characterized as an antimicrobial peptide in a mass spectrometry-based search for cysteine-rich defensin-like peptides in blood (1) and in urine (2). However, both groups showed that hepcidin displays only a weak antimicrobial activity. Further, unlike defensins, which vary in sequence among species, hepcidin is highly conserved from zebrafish to humans. Shortly after hepcidin was described, subtractive hybridization studies comparing the livers of normal and iron overloaded mice established a connection between iron loading and increased hepcidin mRNA (3, 4). The fundamental insight into hepcidin's role in iron homeostasis came in 2004 with the discovery that hepcidin acts to lower iron in the blood by binding to and downregulating the iron transporter, ferroportin (FPN1) (5). FPN1 is the only known transporter that is responsible for the efflux of iron from cells. Downregulation of FPN1 by hepcidin in splenic and hepatic macrophages decreases the ability of macrophages to export recycled iron from senescent rbcs, which constitute the primary source of iron in the plasma. In addition, a high concentration of hepcidin in the blood decreases the transport of iron out of intestinal epithelial cells, further limiting iron in the blood. Control of hepcidin expressionHepcidin is synthesized, processed to an active form, and secreted predominantly by hepatocytes (6, 7). The expression of hepcidin is mediated through the bone morphogenetic protein (BMP) and JAK2/STAT3 signaling pathways (Figure 1). Under nonpathological conditions, iron levels in the body upregulate hepcidin expression. Although the underlying mechanisms are poorly understood, recent studies have documented the essential roles of hemojuvelin (HJV), hereditary hemochromatosis protein (HFE), transferrin receptor 2 (TfR2), and matriptase-2 (MT2, encoded by the gene TMPRSS6) in the process of hepcidin regulation in humans and animal models as well as of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).Intact BMP signaling is essential for hepcidin expression. The canonical BMP-signaling pathway is initiated upon BMP binding to a BMP receptor complex on the cell surface, which activates the receptor kinase to phosphorylate the cytoplasmic proteins SMAD1, SMAD5, and SMAD8. These phosphorylated, receptor-regulated SMADs then form transcription factor complexes with SMAD4, consisting of receptor-regulated SMADs and SMAD4, that translocate into the nucleus to induce the transcription of target genes such as hepcidin (18). In mice, liver-specific disruption of SMAD4 or the BMP receptors ALK2 or ALK3 markedly decreased hepcidin expression, resulting in iron overload (15,19).BMP6. At least 20 BMPs are expressed in mammals. In vitro studies reveal that BMP2, -4, -5, -6, -7, and -9 can robustly induce BMP signaling and markedly increase hepcidin expres...

Association of iron metabolic enzyme hepcidin expression levels with the prognosis of patients with pancreatic cancer

“…Conversely, several studies have shown that iron deprivation inhibits in vitro tumor growth (15). Hepcidin is a key peptide hormone that regulates iron homeostasis in chordates and is produced by the liver in response to inflammatory stimuli and iron overload (16,17). Hepcidin is a small antimicrobial peptide that inhibits iron absorption by enterocytes, iron release from macrophages, and iron transport across the placenta.…”

Portuguese Consensus on the Diagnosis, Prevention and Treatment of Anaemia in Inflammatory Bowel Disease

“…110 The mechanism may involve a decreased production or sensitivity to erythropoietin, 20 inhibition of erythroid precursors 13 and disruption of the iron metabolism mediated by hepcidin. 111 Basseri et al 112 showed a correlation between high levels of IL-6, hepcidin and ferritin and the severity of anaemia.…”

Difficulties of Diagnostics of «competitive» Processes: The Systemic Lupus Erythematosus at the Patient With the Modern Comorbidity. The Clinical Case

“…В ОАК: Эр -3,2*10 12 /л, Hb -91 г/л, Т -258*10 9 /л (N: 150-390), Л -3,8*10 9 /л, лимфо-циты -14% (18-40) / 0,5*10 9 /л (1,2-3,0), п/я -7%, с/я -75%, СОЭ -69 мм/час, ретикулоциты -6 промилле (N: 2-13), просмотр окрашенного мазка периферической крови: гипохромия эритроцитов (++), анизоцитоз смешанный (+), встречаются мега-лоциты и гипохромные макроциты; ОАМ: цвет -жёлтая, прозрачность -мутная, относительная плотность 1010 (N: 1012-1024), реакция -кислая, белок -4,6 г/л (N: 0-0,12), глюкоза -нет, эпите-лий плоский -2-3 в п/з, цилиндры зернистые, вос-ковидные, лейкоцитарные -ед. в п/з, бактерии (+); показателей БАК: глюкоза -7 ммоль/л (N: до 5,5), общий белок -49 г/л (65-85), альбумины -43,6% (46,9-61,4), α 1 -gl -5,31% (2,(2)(3)(4)2), α 2 -gl -15,8% (7,(9)(10)9), β-gl -14,6% (10,2-18,3), γ-gl -20,7% (17,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)4), общий билирубин -9,7 мкмоль/л, прямой би-лирубин -2,2 мкмоль/л, ЩФ -157 Ед/л (до 270), ГГТП -61 Ед/л (до 32), креатинин -128 мкмоль/л (до 106), мочевина -11,6 ммоль/л (до 8,3), мочевая кислота -732 мкмоль/л (до 310), сывороточное железо -4,9 мкмоль/л (6,1), ПТИ -103% (80-110), уровни АЛТ и АСТ -в N; определены уровни прокальцитонина -0,23 нг/мл (до 0,5) и сывороточ-ного ферритина -887 мкг/л (15-150), кровь на си-филис (ЭДС) -отрицательно. ОАМ в динамике на 3 сутки: относительная плот-ность -1003, реакция -кислая, белок -1,9 г/л (0-0,12), лейкоциты -45-55 в п/з, эритроциты из-менённые -10-15 в п/з, глюкоза -нет, эпителий плоский -ед.…”