The liver (Fig. 1) is the central controller of systemic iron homeostasis, the source of plasma hepcidin, and the major iron storage organ. The dual blood supply of the liver from the portal and systemic circulation allows monitoring of both plasma iron in the systemic circulation and newly absorbed iron in the portal circulation. Hepatocytes can acquire iron from plasma transferrin via the transferrin cycle; from hemoglobin−haptoglobin and heme− hemopexin complexes via endocytosis after binding to CD163 and LRP1 receptors, respectively; from lactoferrin, apparently by receptor-mediated endocytosis; and from plasma nontransferrin bound iron (see Fig.1). Plasma non-transferrin-bound iron forms when the rate of iron influx into plasma exceeds the rate of iron acquisition by transferrin. Plasma non-transferrin-bound plasma iron enters specific cells independently of the transferrin mechanism, particularly hepatocytes, pancreatic acinar cells, cardiomyocytes, and anterior pituitary cells, producing toxic accumulations in some forms of iron overload. In mice, the ZRT/IRT-like protein 14 (ZIP14; SLC39A14), whose nonredundant role is as a manganese transporter required for regulating the total amount of manganese in the body, is also the major route for cellular uptake of plasma non-transferrin-bound iron by hepatocytes and pancreatic acinar cells. In the heart, ZIP14 is not required for uptake of plasma non-transferrin-bound iron and iron loading; L- or T-type Ca2+ channels are possible alternative transporters.

Fig1. ACQUISITION, USE, STORAGE, AND EXPORT OF IRON BY HEPATOCYTES. Hepatocytes can acquire iron from plasma transferrin (Tf) via the Tf cycle; from heme–hemopexin complexes via endocytosis after binding to CD91 receptors; from lactoferrin, apparently by receptor-mediated endocytosis; from iron-rich ferritin by TfR1-mediated endocytosis and from plasma non-Tf-bound iron (NTBI) using ZIP14. Iron is used for the synthesis of heme and nonheme enzymes, with any excess stored in ferritin and hemosiderin. Iron is exported through ferroportin and oxidized by ceruloplasmin before being taken up by plasma Tf. See text for details. DMT1, Divalent metal transporter 1; Fe2 Tf, diferric transferrin; FLVCR, feline leukemia virus subgroup C cellular receptor; HO-1, heme oxygenase-1; LRP, low-density lipoprotein receptor-related protein; RHL-1, rat hepatic lectin-1 subunit of the asialoglycoprotein receptor; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TfR1, transferrin receptor 1; ZIP14, Zrt- and Irt-like protein 14 (SLC39A14, solute carrier family 39, member 14). (Reproduced with permission from Graham RM, Chua ACG, Herbison CE, et al. Liver iron transport. World J Gastroenterol. 2007;13:4725.)

The liver functions as the central controller of systemic iron homeostasis by being by far the predominant organ secreting hepcidin into blood circulation. The biologically active 25-amino acid peptide is produced by proteolytic processing of an 84-amino acid prepropeptide by furin. After secretion, hepcidin circulates in plasma weakly bound to α2-macroglobulin and is rapidly cleared by the kidneys or degraded after binding to ferroportin. As detailed earlier, hepcidin controls the entry of iron into plasma by decreasing the number of ferroportin molecules available for iron export from macrophages, hepatocytes, and duodenal enterocytes.

Plasma hepcidin concentrations increase in response to increased iron concentrations in plasma and in response to the amount of iron stored in hepatocytes. A separate regulatory mechanism increases the production of hepcidin during infection or inflammation. Plasma hepcidin concentrations decrease with iron deficiency, hypoxia, and increased erythropoietic requirements for iron, increasing plasma iron. The hepatocyte coordinates the influences of iron, inflammation, and erythropoietic demand to determine hepcidin secretion and thereby the systemic supply of iron. Because plasma iron in the steady state is replaced every 2 to 3 hours, changes in plasma hepcidin that substantially affect iron influx into plasma are followed within a few hours by changes in plasma iron.

Regulation of hepcidin seems to be entirely transcriptional, integrating signals for induction and inhibition of synthesis both from within and outside the hepatocyte.2 Intensive investigation has revealed a complex and still incompletely characterized signaling network for transcriptional regulation of hepcidin (summarized graphically in Fig. 2). The available evidence indicates that major regulators of hepatic hepcidin synthesis include iron (hepatic iron stores, absorbed dietary iron, plasma iron in the systemic circulation), hypoxia, erythropoietic iron requirements, and inflammation and endoplasmic reticulum (ER) stress. Recent studies have found that the control of hepcidin synthesis is further modulated by a variety of other signal transduction pathways, including nutrient sensitive mammalian target of rapamycin (mTOR) and proliferative rat sarcoma/rapidly accelerated fibrosarcoma mitogen-activated protein kinase (Ras/RAF MAPK), signaling1 that link hepcidin regulation to nutrient metabolism, cytokines, growth factors, and cellular proliferation.

Fig2. TRANSCRIPTIONAL REGULATION OF HEPCIDIN EXPRESSION IN HEPATOCYTES. Hepatic hepcidin synthesis is regulated by iron, erythropoietic iron requirements, inflammation, and endoplasmic reticulum (ER) stress. Bone morphogenetic proteins 2 and 6 (BMP2/6) are the key endogenous regulators of hepcidin synthesis, possibly acting as the BMP2/6 heterodimer. BMP2/6 initiates a signaling cascade by binding to the BMP coreceptor hemojuvelin and to two type I and two type II BMP receptors (BMPR I-II) on the surface of hepatocytes. Neogenin may act to stabilize hemojuvelin. BMP2/6 binding is followed by phosphorylation of sons of mothers against decapentaplegic (SMAD)1/5/8 and formation of the SMAD1/5/8–SMAD4 complex, which translocates to the nucleus and activates the promoter of the hepcidin gene (HAMP). TMPRSS6 (transmembrane protease, serine 6; matriptase-2) inhibits BMP2/6 induction of hepcidin synthesis by cleaving hemojuvelin from the cell membrane. HFE (the hemochromatosis protein) interacts with TfR1 and perhaps also with TfR2 to modulate hepcidin synthesis through the BMP6-HJV-SMAD pathway. The erythroid-derived hormone erythroferrone has been identified as a mediator of hepcidin suppression by stress erythropoiesis and acts by binding to BMP2/6 and preventing its access to the BMP receptor complex. The inflammatory cytokine interleukin-6 induces hepcidin expression through a Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway. See text for details. RBC, red blood cells. (Modified from Kroot JJ, Tjalsma H, Fleming RE, et al. Hepcidin in human iron disorders: diagnostic implications. Clin Chem. 2011;57:1650.)

Iron Regulation of Hepcidin Expression

Bone morphogenetic proteins 2 and 6 (BMP2 and 6), members of the transforming growth factor-β (TGF-β) superfamily, are the key endogenous regulators of hepcidin production (see Fig. 2). BMP6 is produced primarily by hepatic sinusoidal endothelial cells in response to hepatocyte iron stores. BMP2 is produced by the same cells. It is required for hepcidin regulation but appears to be less responsive to hepatic iron load. BMP2 and 6, perhaps acting as a heterodimer, initiate a signaling cascade by binding to hemojuvelin (HJV), a membrane glycophosphatidylinositol-linked BMP coreceptor essential for effective induction of hepcidin, and to BMP receptors on the surface of hepatocytes. BMP2/6 binding is followed by phosphorylation of sons of mothers against decapentaplegic (SMAD)1/5/8 and formation of the SMAD1/5/8–SMAD4 complex, which translocates to the nucleus and activates the promoter of the hepcidin gene (HAMP). HJV is a critical potentiator of the BMP2/6-SMAD regulatory pathway. Some muta tions in HJV, the gene for HJV, can profoundly decrease the synthesis of hepcidin and other mutations in HAMP may even completely abolish the synthesis of hepcidin, resulting in juvenile forms of hemochromatosis (types 2 A and 2B, respectively) with severe iron loading.

Neogenin, a Deleted in Colorectal Cancer (DCC) family member, seems to stabilize HJV, thereby enhancing BMP6 signaling and hepcidin expression. Furin, a proprotein convertase, cleaves mem brane-bound HJV to produce a soluble form of HJV that acts as a competitive antagonist of membrane-bound HJV, inhibiting hepcidin activation. TMPRSS6, a transmembrane serine protease, inhibits BMP6 induction of hepcidin synthesis by cleaving HJV and possibly other proteins of the BMPR complex from the cell membrane. A variety of inactivating mutations in the TMPRSS6 gene produce high levels of hepcidin that are responsible for iron-refractory iron-deficiency anemia.

Plasma iron, in the form of diferric transferrin, is believed to modulate hepcidin synthesis through a distinct pathway that involves HFE, an atypical major histocompatibility complex class I protein that forms a complex with β2-microglobulin, transferrin receptor 1, and transferrin receptor 2 (see Fig. 2). Mutations in the genes encoding these proteins, HFE (hemochromatosis gene) and TFR2 (transferrin receptor 2 gene), respectively, are responsible for adult forms of hemochromatosis (types 1 and 3, respectively). In these adult forms of hemochromatosis, hepcidin is produced but does not get appropriately upregulated as iron stores increase; iron loading is generally less severe than in the juvenile forms. The regulatory mechanism may involve the binding of circulating diferric transferrin to transferrin receptor 1 (TfR1), displacing HFE to form a complex with the BMP receptor. TfR2 also interacts with BMP signaling. The two transferrin receptors and HFE may effectively act as a sensor of extracellular concentration of diferric transferrin that modulates BMP signaling.

Erythropoietic Regulation of Hepcidin Expression

Increased erythropoietic demand for iron reduces hepatic hepcidin synthesis and can sometimes override competing influences that induce hepcidin expression, such as iron overload and inflammation. Hemolysis, hemorrhage, and administration of erythropoietin lower circulating hepcidin concentrations. Patients with marked ineffective erythropoiesis, such as those with β-thalassemia intermedia, have very low or absent plasma hepcidin, increased iron absorption, and high plasma iron despite severe iron overload. Neither hypoxia nor erythropoietin decreases hepcidin transcription directly. Studies of earlier candidate media tors, growth differentiation factor 15 (GDF15) and twisted gastrulation protein (TWSG1), have found that neither is involved in the downregulation of hepcidin synthesis after acute blood loss. Erythroferrone, a newly identified hormone produced by erythroblasts in response to erythropoietin, is the physiologic regulator of hepcidin expression that suppresses secretion during stress erythropoiesis. Erythroferrone likely suppresses hepcidin transcription by inhibiting signaling through BMP-SMAD pathway. A specific erythroferrone receptor has not been identified, but there is evidence for a non-receptor mechanism involving direct binding of BMP2/6 by erythroferrone and erythroferrone-mediated interference with BMP2/6 access to the BMP receptor. Still other signal transduction pathways seem likely to be involved in regulating hepatic hepcidin production in response to increased erythropoietic requirements. Erythropoietin-induced increase in transferrin receptor 1 expression on erythroid precursors may selectively deplete its preferred ligand, diferric transferrin, from plasma. As diferric transferrin also functions as an extracellular iron signal for hepcidin regulation, its removal will at least transiently suppress hepcidin.

Inflammatory and Endoplasmic Reticulum Stress-Related Regulation of Hepcidin Expression

 Inflammation increases plasma hepcidin, resulting in the retention of iron within macrophages, reduced iron absorption, and hypoferremia. The inflammatory cytokine interleukin-6 (IL-6) induces hepcidin expression (see Fig. 2). IL-6 activates the Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling path way, stimulating hepcidin production through STAT3 interactions with a STAT3-binding element in the hepcidin promoter. Other cytokines and the BMP6-HJV-SMAD pathway may also be involved. In addition, the acute inflammatory response is linked to ER stress (see Fig. 2), resulting from the accumulation of unfolded or mis folded proteins with disruption of ER homeostasis.

Within hepatocytes and other cells, cytosolic iron is present physiologically in low-molecular-weight forms destined for incorporation into functional compounds or, if present in amounts exceeding cellular requirements, for storage. Recent evidence suggests that protein chaperones and other specialized carriers, membrane transporters, and glutathione provide for the distribution of iron within cells. The cytosolic iron chaperone PCBP1 can deliver excess iron to ferritin, whose structure maintains large amounts of iron in solution in a compact yet bioavailable form, diffusely distributed within the cytosol. A closely related molecule PCBP2 may help transport iron that is destined for cellular export by ferroportin. Cytosolic ferritin is a heteropolymer consisting of 24 subunits of heavy (H) and light (L) peptides that form a hollow sphere into which as many as 4500 atoms of iron may be deposited in an iron core composed of the hydrous ferric oxide mineral ferrihydrite (5Fe2 O3 ⋅9H2 O). Exit of iron from ferritin may occur through gated pores but mainly by autophagy and lysosomal degradation of ferritin. The ferritin cargo receptor NCOA4 delivers ferritin to the autophagic system where its iron content is liberated. A soluble, relatively iron-poor form of ferritin is found in blood plasma. This form is a 24-subunit polymer containing mostly L-ferritin and is derived primarily from macrophages and hepatocytes. Recent studies indicate that iron-loaded ferritin may be released from cells by a non-canonical secretion pathway, with subsequent TfR1 mediated selective reuptake of iron-loaded ferritin by neighboring cells, presumably as a means of distributing iron within tissues to cells that are relatively iron-deficient. This process selectively depletes the iron-loaded form of ferritin from extracellular fluid, leaving relatively iron-poor ferritin in circulation. Serum concentrations of ferritin correlate with iron stores, with exceptions reflecting pathological situations in which the macrophages are much less or much more iron loaded than parenchymal tissue, or situations where ferritin synthesis is primarily driven by inflammation.

At very high iron concentrations, ferritin protein subunits may aggregate, resulting in the formation of amorphous, insoluble masses of hemosiderin that may protect against iron toxicity by sequestering the excess iron away from the cytosol, enclosed within siderosome membranes. Depending on the cellular type and iron supply and use, the half-life of cellular ferritin may range from less than 20 to 96 hours. Hemosiderin characteristically has a much slower cellular turnover than ferritin. Altogether, for short-term storage of iron, cytosolic iron is in rapid equilibrium with soluble, dispersed ferritin, but for long-term sequestration, the aggregates of iron within hemosiderin undergo slow and limited exchange. Nonetheless, with phlebotomy or iron-chelating therapy, all of the iron within hemosiderin deposits eventually can be mobilized.

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قسم الشؤون الفكرية يطلق عددًا خاصًّا من نشرة الخميس في ذكرى شهادة الإمام علي (عليه السلام)

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لصقل مواهبهم وتطويرها.. المجمع العلمي يشرك طلبة الدورات القرآنية في الختمات الرمضانية

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متى تكون الحمى طبيعية؟

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الجهاز المناعي يظهر دورا غير متوقع في صحة العظام

ابتكار من جامعة الشارقة منخفض التكلفة للحماية من الزلازل

اكتشاف تأثير غير متوقع للكاكاو على وظائف الدماغ

باحثون يرصدون أثر تغيّر المناخ في دم البشر

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مواضيع ذات صلة

Intestinal Iron Absorption

Recycling of Erythrocyte Iron by Macrophages

Use of Iron For Erythropoiesis

Essential Features OF Red Blood Cell Homeostasis

sentinel lymph node biopsy (SLNB, Lymphoscintigraphy)

salivary gland nuclear imaging (Parotid gland nuclear imaging)

pulmonary angiography (Pulmonary arteriography)

Fever of Unknown Origin

Biological Markers of Mental Illness

New Biomarkers of Bone Remodeling : Sclerostin

New Biomarkers of Bone Remodeling : RANK-RANKL-OPG

Splenic Abscesses