Hepcidin in Human Iron Disorders: Diagnostic Implications | Clinical Chemistry
The other requirement for iron in erythropoiesis relates to its functional .. between iron and erythropoiesis, where a molecule may be performing a dual role in. also evaluated them in relation to the degree of anemia or polycythemia, and inherent to the relative invalidity of TfR in iron deficiency, the imprecision . ferential absorbance was read in dual wave length mode at and. in a Titertek. sumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and Camaschella C, Pagani A. Iron and erythropoiesis: a dual relationship.
Iron uptake and recycling. Most of the used body iron is recycled from senescent erythrocytes by macrophages, and returned to the bone marrow for incorporation in erythroid precursors.
The liver and RE macrophages function as major iron stores. Importantly, the total amount of iron in the body can be regulated only by absorption, whereas iron loss occurs only passively from sloughing of skin and mucosal cells as well as from blood loss.
This results in the absorption and loss of 1—2 mg iron every day. Hepcidin, a peptide produced in the liver, controls the plasma iron concentration by inhibiting iron export by ferroportin from enterocytes and macrophages. As a consequence, an increase in hepcidin production leads to a decrease in plasma iron concentrations. Hepcidin expression is regulated by body iron status, inflammation, erythroid iron demand, and hypoxia via regulation pathways involving the expression of the genes HFE, transferrin receptor 2 TFR2and hemochromatosis type 2 juvenile HFE2 also known as HJV.
Adapted from In addition to its role in regulating systemic iron metabolism, hepcidin may also contribute to host defense. Hepcidin was originally identified as an antimicrobial peptide 1 Although in vitro studies suggest bacteriocidal effects of hepcidin, these effects would require concentrations higher than those observed in the circulation.
Such concentrations may be achieved locally, for instance in phagosomes of infected macrophages Hepcidin might also contribute indirectly to host defense by reducing plasma iron concentrations. Iron is necessary for microbial growth, and reductions in plasma iron are bacteriostatic. Moreover, hepcidin was found to modulate lipopolysaccharide-induced transcription in both cultured macrophages and in vivo mouse models This latter observation suggests a role for hepcidin in modulating acute inflammatory responses to bacterial infection.
Hepcidin produced by various cell types other than hepatocytes see above may have local effects in these tissues. Although the smaller forms of hepcidin do not elicit a hypoferremic response, it is currently unknown whether they retain other identified biological functions of hepcidin e. Hepcidin Regulation Several physiologic and pathologic processes regulate the synthesis of hepcidin Fig.
Situations in which demand for circulating iron is increased particularly erythropoietic activity elicit a decrease in hepatocellular hepcidin synthesis. These conditions include iron deficiency, hypoxia, anemia, and conditions characterized by increased erythropoietic activity. A decrease in hepcidin results in the release of stored iron and an increase in dietary iron absorption.
On the other hand, infection and inflammation cause an increase in hepcidin synthesis. This increased synthesis leads to a deficiency of iron available for erythropoiesis, and is considered to be the mechanism underlying reticuloendothelial RE iron sequestration, intestinal iron absorption impairment, and low serum iron concentrations characteristic of anemia of chronic disease.
The functional signaling routes by which a iron status, b erythropoietic activity, c hypoxia, and d inflammation affect hepcidin expression are increasingly being investigated. These routes comprise 4 highly interconnected regulatory pathways Fig. Molecular and functional pathways of hepatocyte hepcidin synthesis.
Erythropoiesis and Iron Sulfur Cluster Biogenesis
Three molecular pathways can be distinguished: This proposed model depicts 2 iron signals to hepcidin, 1 mediated by intracellular iron stores Fe and the other by circulating iron Tf-Fe2. Hepatocellular iron stores increase the expression of BMP-6, which serves as an autocrine factor by interacting with surface BMP receptors. The consequent activation of intracellular SMAD proteins transduces a signal to increase hepcidin transcription. HJV is subject to cleavage by furin, which is regulated by iron and hypoxia, to form a soluble component sHJV Under low iron conditions membrane bound HJV is also cleaved by matriptase-2 scissors again weakening the BMP-6 signal.
Extracellular Tf-Fe2 mediates a second iron signal. HFE is then liberated to interact with TfR2. Hypoxia influences liver-specific stabilization of HIF-1, which induces matriptase-2 and the subsequent cleavage of HJV The latter pathway may be synergistic to the increased release of sHJV upon its cleavage by furin under hypoxic conditions.
These pathways have recently been reviewed Circulating transferrin appears to be sensed via a hepatocellular complex, which includes transferrin receptor-1 TfR1TfR2, and hemochromatosis iron protein HFE. Defects in TfR2 and HFE lead to decreased hepcidin concentrations via the extracellular signal-regulated kinases: Intracellular iron stores communicate with hepcidin via BMPs, particularly BMP-6, in a paracrine or autocrine fashion.
These extracellular signaling molecules act on hepatocellular BMP receptors to activate the intracellular SMAD signaling pathway and increase hepcidin transcription. Hemojuvelin HJVa BMP coreceptor 47is crucial for hepcidin expression because various hepcidin regulatory pathways converge at this membrane-bound protein. Under low iron conditions, membrane-bound HJV is cleaved by matriptase-2, a transmembrane protease serine 6, encoded by the transmembrane protease, serine 6 TMPRSS6 6 gene, expressed predominantly in the liver 48 This cleavage by matriptase-2 weakens the BMP signaling.
Erythropoiesis requires considerable amounts of iron, so suppression of hepatic hepcidin synthesis by erythropoietic signals is of great physiological importance. However, how erythropoiesis regulates hepcidin is not clear yet.
The hypothesis that erythropoietin EPO acts directly on hepatocyte receptors in cell culture 51 could not be confirmed in animal models for anemia, which showed that decreased hepcidin expression depends on erythropoiesis and is not directly mediated by EPO 53 Recent observations suggest that the erythropoietic signal may include 1 or more proteins released at sites of active erythropoiesis, i.
Correlations between the expression of TWSG1 expression and serum iron parameters and serum hepcidin concentrations have not yet been determined in humans. Neither of these factors, however, appears to be required to mediate the decrease in hepcidin observed with EPO administration. It is likely that additional erythropoietic factors downregulating hepcidin expression will be identified. Whether HIFs directly bind to the hepcidin promoter is currently controversial. However, there are indirect mechanisms by which HIFs may regulate hepcidin expression.
Increased HIF activity is associated with increased matriptase-mediated cleavage hemojuvelin and thus decreased hepcidin expression Moreover, the systemic iron regulation by the hepcidin-ferroportin axis acts in harmony with the enterocyte cellular iron homeostasis control system.
3 Relationship Between Iron and Erythropoiesis - Semantic Scholar
Hepcidin expression is also increased by oxidative or endoplasmic reticulum stress. There are multiple potential opportunities for cross communication among these pathways, and experimental evidence shows that these pathways do not function completely independently of each other. Serum hepcidin concentrations appear to be determined by the relative strengths of the individual regulators. In an attempt to delineate relative strengths of these regulators in patients with iron metabolism disorders, we constructed an algorithm to predict relative hepcidin concentrations based on certain serum parameters C-reactive protein, Tf saturation, and soluble TfR that reflect inflammation, serum iron, and erythropoietic regulatory pathways This algorithm provided insight into the interrelation of these pathways by showing that hepcidin inhibition by erythropoiesis strongly interferes with hepcidin upregulation by iron and that inflammation strongly increases hepcidin regardless of iron status and erythropoietic activity.
Abstract Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. Heme synthesis depends on iron through its dependence on iron sulfur Fe-S cluster biogenesis.
metabolismo do ferro e eritropose
These Fe-S biosynthesis proteins are highly expressed in erythroid tissues, and deficiency of each of these proteins has been shown to cause anemia in zebrafish model.
GLRX5 is involved in the production and ABCB7 in the export of an unknown factor that may function as a gauge of mitochondrial iron status, which may indirectly modulate activity of iron regulatory proteins IRPs. ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase, the enzyme producing lipoate for pyruvate dehydrogenase complex PDC.
PDC and aconitase are involved in the production of succinyl-CoA, a substrate for heme biosynthesis. Thus, many steps of heme synthesis depend on Fe-S cluster assembly. Erythropoiesis Erythropoiesis, the manufacture of red blood cells or erythrocytesmainly occurs within bone marrow in human adults, for review see [ 1 ].
3 Relationship Between Iron and Erythropoiesis
In erythropoiesis, there is a stepwise differentiation of cell types, beginning with multipotent hematopoietic stem cells which successively mature into common myeloid progenitor cells, proerythroblasts, erythroblasts, and finally into mature erythrocytes [ 2 ].
Erythropoiesis is stimulated by the hormone, erythropoietin EPOfor review see [ 3 ], which enhances proliferation and differentiation of the erythroid cells by blocking apoptosis of erythroid progenitors, as is reviewed elsewhere, for review see [ 4 — 8 ].
Hemoglobinization results from the production of hemoglobin, which requires synthesis of heme.
- Metabolismo do ferro e eritropoiese
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- Iron and erythropoiesis: a dual relationship.
Heme is synthesized by an eight step enzyme-catalyzed pathway,in which the final step is the insertion of an iron into protoporphyrin IX to form a protoheme, for review see [ 910 ]. Iron homeostasis during erythropoiesis is highly regulated to synchronize synthesis of heme and globin and to avoid the potential toxicity caused by accumulation of excess iron or heme. Systemic Iron Metabolism and Regulation of Hepcidin Expression by EPO and Other Factors Iron in food is absorbed in the duodenum, from which it is released into the circulation via ferroportin, the iron exporter on basolateral membranes of duodenal enterocytes.
Most of the daily iron supply in the human body comes from phagocytosis of senescent red blood cells by macrophages in the spleen, liver, and bone marrow.
Macrophages recycle iron by metabolizing heme and releasing the free iron into the circulation via the membrane-bound ferrous iron transporter, ferroportin [ 11 — 13 ]. The ferroportin-mediated release of iron is therefore a key regulation point of systemic iron metabolism. Hepcidin is a small peptide synthesized mainly in the liver that modulates the abundance of ferroportin at the cellular membrane of cells that release iron, for review see [ 14 — 16 ].
Hepcidin is the master regulator of systemic iron homeostasis: The transcription of hepcidin is complex and is finely tuned by a number of different signal transduction pathways, for review see [ 1417 — 19 ]. To coordinate iron metabolism to meet the demands of erythropoiesis, hepcidin expression is regulated by EPO, the erythropoiesis stimulator, and also possibly by growth differentiation factor 15 GDF15 and twisted gastrulation TWSG1soluble peptides which are directly produced by erythroblasts [ 2021 ].
GDF15 secretion from maturing erythroblasts may inhibit hepcidin mRNA expression in hepatocytes, which would therefore allow more release of iron into plasma from the duodenum and macrophages to support erythropoiesis. However, this potential role of GDF15 remains unproven, as GDF15 has failed to suppress hepcidin expression in cellular models [ 2324 ]. In thalassemia syndromes, GDF15 is overexpressed, and its proposed repression of hepcidin expression leads to iron overload [ 20 ].
IRP2 is degraded in iron replete conditions whereas it is stabilized in cells that are iron-depleted, and stabilized IRP2 acts as a second IRE-binding protein. Erythropoiesis depends on ample iron supplies, and the process of erythropoiesis is regulated in several ways by iron metabolism. Erythropoiesis is driven by EPO, a hormone synthesized mainly in renal interstitial cells.
In hypoxic cells, both HIF1 and HIF2 proteins are stabilized, and transcription of their target genes increases [ 32 ]. However, in cells that are also iron deficient, translation and synthesis of HIF2 would be expected to be repressed by IRP binding.
More directly, erythroblasts are themselves significantly dependent on proper iron homeostasis controlled by IRP2 [ 3334 ] and on successful iron acquisition mediated by transferrin receptor 1 TfR1 [ 35 ] and mitoferrin-1 or SLC25A37 [ 3637 ], as shown by anemias that develop when they are deficient in model organisms. The important role of TfR1 in iron acquisition by erythroblasts is also supported by studies in the zebrafish model system. TfR1b is expressed primarily in nonerythroid tissues, and genetic ablation of TfR1b causes growth retardation and brain necrosis without adversely affecting hemoglobinization.
In contrast, TfR1a is expressed specifically in erythroid precursor cells, and its ablation causes hypochromic microcytic anemia [ 35 ].
Since mammals express a single TfR1 gene ubiquitously, which is responsible for transferrin iron uptake in all tissues including erythroid tissues, it is not surprising that disruption of the TfR1 gene in mice affects both erythropoiesis and neurologic development, and deletion of TfR1 in mice is embryonically lethal [ 38 ].
Mitoferrin 1 is the principle iron importer on the inner membrane of mitochondria for erythroblasts. It is highly expressed in hematopoietic tissues, and deficiency of mitoferrin 1 impairs iron incorporation into heme, resulting in hypochromic anemia and erythroid maturational arrest in zebrafish [ 3637 ].
Iron Sulfur Cluster Fe-S Biogenesis for Erythropoiesis Iron sulfur clusters Fe-S are synthesized in human cells by a mitochondrial machinery and also by an independent cytosolic machinery, which involve at least 20 proteins in total, for review see [ 39 ]. It is thought that frataxin provides the iron by binding iron loosely to an acidic ridge [ 40 ].
Under conditions that impair mitochondrial Fe-S cluster synthesis, iron is imported into mitochondria with high priority, which in turn results in cytosolic iron deficiency and impairment in cytosolic Fe-S cluster synthesis [ 414449 ]. Due to the importance of IRP proteins in iron homeostasis and the involvement of Fe-S clusters in modulating IRP1 activity, the process of Fe-S cluster biogenesis is actually central to the regulation of mammalian cellular iron homeostasis [ 39 ].
Defects in human Fe-S cluster biogenesis cause many different diseases, including anemia [ 254750 ].
ABCB7 is an ATP-binding cassette ABC transporter located on the inner membrane of mitochondria, for review see [ 51 — 53 ], which is essential to heme synthesis and erythropoiesis, as revealed by development of sideroblastic anemia in patients with ABCB7 mutations [ 54 — 56 ].
The ABCB7 deficiency results in iron accumulation in mitochondria, reduced heme synthesis in erythrocytes and ineffective erythropoiesis. Perhaps due to its high expression in cerebellum in addition to bone marrow, patients with ABCB7 deficiency also have ataxia [ 5758 ].
Atm1, the ABCB7 homologue in yeast, has been thought to be a member of the proposed Fe-S cluster export machinery in mitochondrial membranes. The compound exported by Atm1 was originally hypothesized to be an Fe-S cluster, for review see [ 5259 ]. As research progressed, and Fe-S synthesis proteins were identified in the cytosol, it was hypothesized that the iron for cytosolic Fe-S assembly was acquired from the cytosol, but that the Atm1 substrate contained a specific type of sulfur that was required for cytosolic Fe-S assembly, for review see [ 60 ].
In human cells, although its activity is not required for Fe-S cluster biogenesis in mitochondria, the unknown substrate transported by ABCB7 appears to be required for the maintenance of iron homeostasis in cytosol, which may in turn affect the Fe-S cluster biogenesis process in cytosol [ 39 ].
Another possibility is that the product exported by ABCB7 perhaps represents a gauge of mitochondrial iron status that contributes to regulation of mitochondrial iron homeostasis. When production or export of this unknown ABCB7 substrate is disturbed, the cell responds as though mitochondria were iron depleted, and efforts to rectify the misperceived state of mitochondrial iron depletion result in actual mitochondrial iron overload and cytosolic iron deficiency [ 586162 ].
But it is thus far unclear at which step ABCB7 function affects heme synthesis. It has been suggested that ABCB7 may physically interact with ferrochelatase and somehow support its activity [ 54 ]. Based on the finding that Mdl1, an ABC7-like transporter, is actually a mitochondrial peptide exporter [ 64 ], and that the substrate of Atm1 proteins is cysteine rich [ 65 ], it is possible that this substrate may be a cysteine-rich small peptide, which signals the rest of the cell about the mitochondrial iron status.Ethical Dilemmas and Dual Relationships