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Hepcidin and Disorders of Iron Metabolism
Abstract
The hepatic peptide hormone hepcidin is the principal regulator of iron absorption and its tissue distribution. Pathologically increased hepcidin concentrations cause or contribute to iron-restrictive anemias including anemias associated with inflammation, chronic kidney disease and some cancers. Hepcidin deficiency results in iron overload in hereditary hemochromatosis and ineffective erythropoiesis. The hepcidin-ferroportin axis is the principal regulator of extracellular iron homeostasis in health and disease, and is a promising target for the diagnosis and treatment of iron disorders and anemias.
... The majority (21e27 mg) of this iron is derived from recycling senescent erythrocytes by macrophages in the reticuloendothelial system, and only 1e2 mg per day is derived from intestinal absorption [73,74]. Daily iron loss is about 1e2 mg, predominantly through desquamation of epithelial cells of skin and intestines, and also minor blood losses which could be balanced by dietary sources and intestinal absorption [75]. Figure 3 shows the normal iron hemostasis and metabolism. ...
... Hepcidin inhibits intestinal iron uptake through binding to ferroportin [83,84]. Hepcidin levels are higher during iron loading and inflammation, and lower during iron deficiency and increased erythropoietic activity [75]. ...
... Although the increase in iron levels in menopause is considered within normal physiologic range, potential health problems in females (and in middle aged males) could be linked to this increase, which in turn can cause organ damage [74,75]. For instance, iron intervenes in the pathogenesis of many diseases such as ischemic heart disease, cancer, diabetes, infections, and neurodegenerative disorders [71,76]. ...
... "Inflammaging", is a term used to describe the phenomenon of lowgrade inflammation that is associated with aging. [8] This mild pro-inflammatory condition is assume to evoke a chronic elevation of circulating hepcidin which will lead to an impairment in the availability of plasma iron, limitation in hemoglobin synthesis and development of anemia of inflammation [10]. ...
... Of the studied elderly anemic patients, all of them (100 %) had high serum hepcidin level. Mean serum hepcidin level was (214.10 ng/ml), and (50.17 ng/ml) in elderly patients and controls respectively as shown in (table-1 [10] . Also elderly patients with iron deficiency anemia and high hepcidin this was similar to the findings of Wendy P.J. den Elzen et al. (2009) who found that aging is often associated with a low grade pro-inflammatory state [1]. ...
... This was similar to the finding in Ganz et al. (2010), who found that inappropriately elevated hepcidin and the resulting hypoferremia are also thought to play a pathogenic role in the developmentof the common forms of ironrestricted anemia [10], those associated with infections and inflammatory disorders including autoimmune diseases and some cancers. In these conditions, multiple cytokines are implicated in increasing hepcidin synthesis, including interleukin IL-6, IL-1, IL-22, and several members of the transforming growth factor β superfamily. ...
Hepcidin, a regulator of iron recycling and absorption, is a small peptide created by the hepatocytes when there is an increase in body iron and inflammation. It is regarded as a master regulator for the metabolism of iron. Hepcidin decreases iron absorption from food by decreasing the transportation of iron across the enterocytes in the gut mucosa. Hepcidin decreases iron escape from macrophages, which are considered as the main site for storage of iron and decreases iron escape from the liver. The aim of this study is to explore the diagnostic value of hepcidin in elderly patients with iron deficiency anemia and anemia of chronic disease. Anemia was defined according to criteria of the World Health Organization (hemoglobin level <13 g/dL for men and hemoglobin <12 g/dL for women). Thirty elderly patients (Age 65 years and above) with anemia were collected randomly from the National center of Hematology and from Al-Karama Hospital. Together with thirty age and sex matched healthy volunteers were collected as a control. History was taken and physical examination was done. Blood samples were taken; hematological parameters were estimated for the two groups. We found strong correlation between serum hepcidin and body iron status. High hepcidin level was detected in elderly patients with anemia of inflammation.
... Our study demonstrates similar findings in the setting of a HFD, supporting a more complex and varied response to iron regulation in the liver, further supporting the need for investigation into BXD inbred strain differences in this context. Hepcidin is a negative regulator of iron absorption by means of ferroportin, the only known iron exporter, degradation [32][33][34]. HFD-associated ...
... Our study demonstrates similar findings in the setting of a HFD, supporting a more complex and varied response to iron regulation in the liver, further supporting the need for investigation into BXD inbred strain differences in this context. Hepcidin is a negative regulator of iron absorption by means of ferroportin, the only known iron exporter, degradation [32][33][34]. HFD-associated inflammation also impacts hepcidin expression and iron homeostasis, ultimately leading to iron dysregulation, which has been associated with metabolic disease, type II diabetes mellitus, and cardiovascular disease [35,36]. Interestingly, adipose iron concentrations were increased due to a HFD for all biological groups except for B6J females, for which iron concentrations were significantly reduced as a result of a HFD. ...
The objective of this study was to determine the influence of sex and strain on the dysregulation of trace element concentration and associative gene expression due to diet induced obesity in adipose tissue and the liver. Male and female C57BL/6J (B6J) and DBA/2J (D2J) were randomly assigned to a normal-fat diet (NFD) containing 10% kcal fat/g or a mineral-matched high-fat diet (HFD) containing 60% kcal fat/g for 16 weeks. Liver and adipose tissue were assessed for copper, iron, manganese, and zinc concentrations and related changes in gene expression. Notable findings include three-way interactions of diet, sex, and strain amongst adipose tissue iron concentrations (p = 0.005), adipose hepcidin expression (p = 0.007), and hepatic iron regulatory protein (IRP) expression (p = 0.012). Cd11c to Cd163 ratio was increased in adipose tissue due to HFD amongst all biological groups except B6J females, for which tissue iron concentrations were reduced due to HFD (p = 0.002). Liver divalent metal transporter 1 (DMT-1) expression was increased due to HFD amongst B6J males (p < 0.005) and females (p < 0.004), which coincides with the reduction in hepatic iron concentrations found in these biological groups (p < 0.001). Sex, strain, and diet affected trace element concentration, the expression of genes that regulate trace element homeostasis, and the expression of macrophages that contribute to tissue iron-handling in adipose tissue. These findings suggest that sex and strain may be key factors that influence the adaptive capacity of iron mismanagement in adipose tissue and its subsequent consequences, such as insulin resistance.
... Zat besi diabsorpsi oleh enterosit bagian membrane apikal melalui DMT- (Ganz and Nemeth, 2011;Papanikolaou and Pantopoulos, 2017;K.Singh, 2018). Zat besi dalam makanan dapat berupa bentuk inorganic ferric (Fe3+), atau ion ferrous (Fe2+) dari sumber non hewani, (Ganz and Nemeth, 2011;Finberg, 2013;Kim and Nemeth, 2016;Papanikolaou and Pantopoulos, 2017). ...
... Zat besi diabsorpsi oleh enterosit bagian membrane apikal melalui DMT- (Ganz and Nemeth, 2011;Papanikolaou and Pantopoulos, 2017;K.Singh, 2018). Zat besi dalam makanan dapat berupa bentuk inorganic ferric (Fe3+), atau ion ferrous (Fe2+) dari sumber non hewani, (Ganz and Nemeth, 2011;Finberg, 2013;Kim and Nemeth, 2016;Papanikolaou and Pantopoulos, 2017). ...
Anaemia become the complication of chronic kidney disease (CKD) which was caused by decreasing of erythropoietin. Erythropoietin stimulating agent (ESA) therapy is one of therapy to overcome the problem, but until 34% of patients have lack of response to ESA treatment. Anaemia in CKD related to the worsen of the diseases, quality of life, and mortality of patients. Decreasing of the response to erythropoietin need to be evaluated to correct anaemic condition. This review is aim to explain the risk factor for erythropoietin resistance. The literature for this review was collected through PUBMED and google scholar. Erythropoietin is glycoprotein secreted 90% by interstitial cells of kidney and 10% by liver cells. The functions of erythropoietin are stimulate the proliferation and cells differentiation in bone marrow, and enhance erythropoiesis. Renal damage can inhibit the secretion of erythropoietin. In patients with ESA treatment, risk factors for resistance are iron deficiency, inadequate haemodialysis, inflammation, hyperparathyroid, nutrition disturbance, antibody mediated Pure Red Cell Aplastic (PRCA). The risk factor can be influenced by genetic variation. Conclusion of this review, there are several factor that influence the response of erythropoietin in hemodialisa patients. Hence, study related anaemia in CKD need further study to optimalize the treatment.
... It is worth noting that an imbalance between the anti-and proinflammatory responses might modify the iron metabolism by affecting the hepcidin expression [11]. Hepcidin is a hormone that blocks iron absorption by the intestines, and its liberation from the liver and other tissues [12]. Moreover, a high serum iron can also stimulate hepcidin expression in a mechanism that involves transferrin receptor 2 [13]. ...
... Moreover, a high serum iron can also stimulate hepcidin expression in a mechanism that involves transferrin receptor 2 [13]. Proinflammatory cytokines stimulate hepcidin biosynthesis, which was confirmed by in vivo and in vitro studies [12,14]. Collectively, the available data indicate that the serum hepcidin levels are controlled by proinflammatory cytokines and serum iron. ...
The current study aimed to examine the impact of the training load of two different training camps on the immunological response in tennis players, including their iron metabolism. Highly ranked Polish tennis players, between the ages of 12 and 14 years, participated in two training camps that were aimed at physical conditioning and at improving technical skills. At baseline and after each camp, blood samples were analyzed, and the fatigue was assessed. The levels of pro- and anti-inflammatory indicators, iron, and hepcidin were determined. The levels of the heat shock proteins, (Hsp) 27 and 70, were also measured. All the effects were evaluated using magnitude-based inference. Although the training camps had different objectives, the physiological responses of the participants were similar. The applied programs induced a significant drop in the iron and hepcidin levels (a small-to-very-large effect) and enhanced the anti-inflammatory response. The tumor necrosis factor α levels were elevated at the beginning of each camp but were decreased towards the end, despite the training intensity being medium/high. The changes were more pronounced in the female players compared to the male players. Altogether, the results suggest that low-grade inflammation in young tennis athletes may be attenuated in response to adequately designed training. To this end, the applied physical workload with a controlled diet and rest-controlled serum iron levels could be the marker of well-designed training.
... Hepcidin constitutes an acute phase liver-derived protein, responsible for maintaining iron (Fe) homeostasis through both local and systemic impact (1,2). Hepcidin triggers the internalization and degradation of ferroportin (the major Fe transporter) which results in a decrease in serum Fe level (3). ...
... Iron, in turn, is a crucial ion for heme synthesis, which is a key hemoglobin (HB) component, essential for red blood cells (RBC) production. Iron metabolism is controlled by hepcidin on three levels: absorption in the duodenum, release from macrophages, and from hepatocytes (2). Furthermore, hepcidin is regulated by serum Fe level and hepatic Fe stores, representing a homeostatic feedback loop (4)(5)(6). ...
Hepcidin is a protein responsible for maintaining iron (Fe) homeostasis. Data regarding the role of hepcidin in the pathomechanism of Fe balance disturbances associated with acromegaly (AG) are scarce. The aim of the study was to assess the impact of alterations in complete blood count parameters, Fe homeostasis, gonadal status and GH/IGF-1 on the level of hepcidin in AG patients. The study evaluated the differences in hepcidin concentration and iron homeostasis between patients newly diagnosed with AG in comparison to healthy control subjects (CS). We prospectively enrolled 25 adult patients newly diagnosed with AG and 25 healthy volunteers who served as CS. The level of hepcidin was measured using the Hepcidin 25 (bioactive) hs ELISA, which is a highly sensitive enzyme immunoassay for the quantitative in vitro diagnostic measurement (DRG Instruments GmbH, Germany). The median of hepcidin concentration in the serum of patients with AG was significantly lower 9.8 (6.2–18.2) ng/ml as compared to CS 21.3 (14.3–34.0) ng/ml (p = 0.003). In the AG group, a statistically significant negative correlation between hepcidin and IGF-1 (rho = −0.441) was observed. Our study demonstrated a decreased hepcidin level in AG patients in comparison to CS what may have a potentially protective effect against anemia through an increased bioavailability of Fe. Additionally, GH may have a positive direct or indirect effect on erythropoiesis. Further studies on larger patient groups are necessary in order to clarify the exact role of hepcidin in the regulation of erythropoiesis in the excess of GH/IGF-1.
... [18][19] En los mamíferos la hormona hepcidina (sintetizada en y liberada por el hígado) es la principal reguladora del metabolismo del hierro. 20 Esta hormona regula la ferroportina: [21][22] un transportador celular de hierro ubicado en la membrana basolateral del enterocito. Luego de la unión con la ferroportina, la hepcidina media la internalización, degradación y posterior liberación del hierro desde el epitelio intestinal hacia la circulación. ...
Introducción: Los estados deficitarios de hierro afectan la funcionalidad del sistema inmune, y con ello, la capacidad del organismo para repeler exitosamente las infecciones microbianas.
Objetivo: Examinar la participación del hierro en la funcionalidad del sistema
inmune. Métodos: La literatura especializada acumulada en los últimos 5 años fue revisada mediante palabras clave selectas para recuperar artículos publicados sobre la importancia del hierro en el adecuado funcionamiento del sistema inmune.
Resultados: A los fines y objetivos de la presente revisión temática se identificaron, y se recuperaron, +100 artículos de diverso tipo distribuidos entre contribuciones originales, revisiones temáticas, y comunicaciones breves; sobre la participación del hierro en la organización, la funcionalidad y la regulación del sistema inmune. El hierro es esencial para la actividad del sistema inmune. Importantes actores celulares del sistema inmune dependen del mineral
para la proliferación, maduración, diferenciación, especialización y expresión de sus funciones. El hierro es también determinante para la articulación efectiva de las 2 ramas del sistema inmune, y la regulación de su actividad. Los estados deficitarios de hierro afectan profundamente la inmunidad del cuerpo. Los organismos patógenos pueden desarrollar mecanismos para secuestrar hierro y utilizarlo en su propio beneficio. Una alimentación saludable, equilibrada, variada e inocua aseguraría ingresos óptimos de hierro, y contribuiría a la integridad y funcionalidad del sistema inmune. La suplementación mineral
estaría justificada en aquellos casos donde las deficiencias preexistentes del mineral podrían suponer un riego aumentado de disfuncionalidad inmune e inmunocompromiso. Sin embargo, la suplementación mineral no sería efectiva en presencia de inflamación, y podría conducir a cuadros de intoxicación igualmente lesivos para la inmunidad y la salud del sujeto. La infección por el virus SARS Cov-2 (causante de la Covid-19) afecta profundamente la homeostasis del hierro, y por esta vía, la integralidad y funcionalidad del sistema inmune.
Conclusiones: La homeostasis del hierro es esencial para la inmunidad. Los estados deficitarios de hierro resultan en la desregulación del sistema inmune, el inmunocompromiso, y un mayor riesgo de colonización e infección microbianas. El aseguramiento de un estado nutricional adecuado contribuye a la integridad y funcionalidad de la respuesta inmune.
... Iron is a vital trace element required to maintain normal cellular physiology. In mammalian cells, iron is stored within ferritin, a multiprotein complex of 24 subunits with varying tissue-specific composition of two subunit types, heavy ferritin (FTH) and light ferritin (FTL), that prevents cellular iron cytotoxicity (1,2). Ferritin is mostly found inside cells; however, during hepatic inflammation and the development of chronic liver disease (such as non-alcoholic steatohepatitis or chronic viral hepatitis B or C), excessive concentrations of circulating ferritin (hyperferritinemia) often exist, which can reflect saturated body iron stores (in hemochromatosis) (3) or act as an indicator of chronic liver disease severity (3)(4)(5)(6). ...
Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of Il1b , NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from Icam1 −/− or Nlrp3 −/− mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.
... [22][23][24] Hepcidin, a coursing peptide hormone, is the key controller of both iron retention notwithstanding the dissemination of iron all through the body, incorporating into plasma. [25][26][27] Hence, intense admissions of in excess of 20 mg/kg iron from enhancements or drugs can prompt gastric bombshell, clogging, queasiness, stomach agony, heaving, and faintness, particularly if sustenance is not taken in the meantime. [8,28,29] Taking enhancements containing 25 mg natural iron or more can likewise decrease zinc ingestion and plasma zinc fixations. ...
Risks of Iron Supplements
... Therefore, it is suggested that IGF1 could be related to liver iron homeostasis. The hepcidin level reflects the bioavailability of iron in the body [59,60]. An increasing number of cytokines, including growth hormone, sex hormones, growth differentiation factor 15, hepatocyte growth factor, and epidermal growth factor, have been shown to influence hepcidin level. ...
Acute liver failure (ALF) is a significant global issue with elevated morbidity and mortality rates. There is an urgent and pressing need for secure and effective treatments. Ferroptosis, a novel iron-dependent regulation of cell death, plays a significant role in multiple pathological processes associated with liver diseases, including ALF. Several studies have demonstrated that mesenchymal stem cells (MSCs) have promising therapeutic potential in the treatment of ALF. This study aims to investigate the positive effects of MSCs against ferroptosis in an ALF model and explore the underlying molecular mechanisms of their therapeutic function. Our results show that intravenously injected MSCs protect against ferroptosis in ALF mouse models. MSCs decrease iron deposition in the liver of ALF mice by downregulating hepcidin level and upregulating FPN1 level. MSCs labelled with Dil are mainly observed in the hepatic sinusoid and exhibit colocalization with the macrophage marker CD11b fluorescence. ELISA demonstrates a high level of IGF1 in the CCL 4+MSC group. Suppressing the IGF1 effect by the PPP blocks the therapeutic effect of MSCs against ferroptosis in ALF mice. Furthermore, disruption of IGF1 function results in iron deposition in the liver tissue due to impaired inhibitory effects of MSCs on hepcidin level. Our findings suggest that MSCs alleviate ferroptosis induced by disorders of iron metabolism in ALF mice by elevating IGF1 level. Moreover, MSCs are identified as a promising cell source for ferroptosis treatment in ALF mice.
... Our study focused on the tubular and glomerular functions of β-TM patients and also comparing those functions with healthy children. Our patient group had significantly higher levels of urea and eGFR than the control group compatible with the study of Mahmoud et al also declaring We also studied EPO and its relation with renal dysfunction as there studies analyzing renoprotective effects of EPO or EPO as a supportive treatment in TM as well as EPO's contribution to iron overload in TM patients by stimulating dietary iron absorption (9)(10)(11)(29)(30)(31)(32). EPO is a glycoprotein, the cardinal hematopoietic growth factor regulating red blood cell production by promoting the survival, proliferation and differentiation of erythroid progenitor cells in the bone marrow. ...
Talasemiler, hemoglobinin globin zincirlerinin sentezini etkileyen mutasyonlardan kaynaklanan heterojen bir kalıtsal bozukluk grubudur. β-TM hastalarında hem glomerüler hem de proksimal tübüler hasarın kanıtı gözlenir. Eritropoietin (EPO), eritroid progenitör hücrelerin çoğalmasını teşvik eden ve birçok organda yeni keşfedilen reseptörlerle kırmızı kan hücrelerinin üretimini artıran, eritropoezin temel düzenleyicilerinden biridir. β-hemoglobinopatilerde tedavinin bir parçası olarak EPO'yu öneren çalışmalardan ve EPO'nun tübüler disfonksiyon ve glomerüler hasarı azaltmada anlamlı etkilerinin olduğu daha fazla çalışmadan ilham alan çalışmamız, β-TM hastalarının tübüler ve glomerüler böbrek fonksiyonlarını ve böbrek fonksiyonlarını değerlendirmeyi amaçladı. EPO durumu.
... Hypoferremia matched to previous results reported by Tan et al. (2019) who recorded decrease in serum iron during Salmonella infection. A common mechanism of hypoferremia of inflammation is cytokine driven increase in hepcidin (Nicolas et al., 2002) that down regulates ferroprotein and thereby decrease iron flow into extracellular fluid from all its source and hinder the gut from absorbing iron from the blood stream (Ganz and Nemeth, 2011). At the same time, the observed decrease in TIBC agrees with Faruqi and Mukkamalla (2023) who reported that TIBC levels decrease in multifactorial anemias or anemia of chronic inflammation. ...
The current study evaluated the efficacy of Selenium Nanoparticles (Se-NPs) on hemato-biochemical, anti-
oxidant biomarkers, and immunological responses induced by S. Typhimurium in broiler chickens. Chicks
(N=120) were divided into six groups. Group 1: received no treatment and set as a control group. Group 2: fed
Se-NPs enriched diet (0.5 mg/kg diet). Group 3: subjected to oral challenge with 3.5x108
CFU/mL/1 ml/bird
of S. Typhimurium. Group 4: administrated Se-NPs (0.5 mg/kg diet) then on day 21 was subjected to 3.5x108
CFU/mL/1 ml/bird of S. Typhimurium. Group 5: vaccinated by a SERVAC Tri Sal. 0.1ml subcutaneous (s/c)
injection on day 3 then subjected to 3.5x108
CFU/mL/1 ml/bird of S. Typhimurium on day 21. Group 6: treat-
ed from day 1 with Se-NPs (0.5 mg/kg diet) till the end of the experiment and vaccinated by a SERVAC Tri
Sal. 0.1ml (s/c) on day 3 and then subjected to 3.5x108
CFU/mL/1 ml/bird of S. Typhimurium on day 21. The
results showed that S. Typhimurium significantly decreased erythrogram, lymphocytes count, total protein,
albumin, A/G ratio, glucose, cholesterol, triglyceride, serum iron, and TIBC, GPX, SOD, TAC, and IL-10
expression compared to the control. Meanwhile, S. Typhimurium significantly increased TLC, heterophils,
monocytes, serum ferritin, liver enzymes (ALT, AST), renal products (creatinine, uric acid), MDA, IL6 ex-
pression. Conversely, the dietary Se-NPs supplementation and/or Salmonella vaccine to the infected broiler
induced, to various degrees, improvement in hemato-biochemical, antioxidant biomarkers, and proinflamma-
tory responses compared to challenged group. In conclusion, dietary Se-NPs supplementation offered a direct
protection against S. Typhimurium infection for sustaining poultry production and correspondingly protecting
human health.
... Iron metabolism is systemically regulated by the hormone hepcidin, encoded by the hepcidin antimicrobial peptide (HAMP) gene (1,2) . Hepcidin is secreted by the liver to negatively regulate cellular iron efflux by binding to, occluding and signalling for the lysosomal degradation of ferroportin, the only known mammalian cellular exporter of iron (3,4) . ...
The iron-regulatory hormone hepcidin is transcriptionally up-regulated by gluconeogenic signals. Recent evidence suggeststhat increases in circulating hepcidin may decrease dietary iron absorption following prolonged exercise, however evidence is limited on whether gluconeogenic signals contribute to post-exercise increases in hepcidin. Mice with genetic knockout of regulated in development and DNA response-1 (REDD1) display greater glycogen depletion following exercise, possibly indicating greater gluconeogenesis. The objective of the present study was to determine liver hepcidin, markers of gluconeogenesis and iron metabolism in REDD1 knockout and wild-type mice following prolonged exercise. Twelve-week-old male REDD1 knockout and wild-type mice were randomised to rest or 60 min treadmill running with 1, 3 or 6 h recovery ( n = 5–8/genotype/group). Liver gene expression of hepcidin ( Hamp ) and gluconeogenic enzymes ( Ppargc1a , Creb3l3 , Pck1 , Pygl ) were determined by qRT-PCR. Effects of genotype, exercise and their interaction were assessed by two-way ANOVAs with Tukey's post-hoc tests, and Pearson correlations were used to assess the relationships between Hamp and study outcomes. Liver Hamp increased 1- and 4-fold at 3 and 6 h post-exercise, compared to rest ( P -adjusted < 0⋅009 for all), and was 50% greater in REDD1 knockout compared to wild-type mice ( P = 0⋅0015). Liver Ppargc1a , Creb3l3 and Pck1 increased with treadmill running ( P < 0⋅0001 for all), and liver Ppargc1a , Pck1 and Pygl were greater with REDD1 deletion ( P < 0⋅02 for all). Liver Hamp was positively correlated with liver Creb3l3 ( R = 0⋅62, P < 0⋅0001) and Pck1 ( R = 0⋅44, P = 0⋅0014). In conclusion, REDD1 deletion and prolonged treadmill running increased liver Hamp and gluconeogenic regulators of Hamp , suggesting gluconeogenic signalling of hepcidin with prolonged exercise.
... Similarly, metal control is tightly regulated by cells (homeostasis) due to their role in processes such as cell respiration, growth, enzymatic reactions, cell proliferation, and immune function. Alteration on this homeostasis can be associated with the initiation of important pathological conditions like diabetes or cancer (Ganz & Nemeth, 2011;Jansen, Karges, & Rink, 2009;Lichten & Cousins, 2009;Turski & Thiele, 2009). Thus, the measurement of cell-to-cell transient changes in metal ion concentrations may lead to the generation of "signatures" representing how cells control levels of metal ions and how they influence cellular function. ...
... Hepcidin, initially recognized as an anti-microbial peptide, is predominantly synthesized in liver [14] and acts as a key negative regulator of iron metabolism [15,16]. The matured hepcidin, a 25 amino acid peptide, binds to the sole iron exporter ferroportin (Fpn) and leads to its internalization and degradation [17]. ...
... Hepcidin was higher at initial and did not diminish after 6 months of OL-HDF and correlated with positively with IL-6. It has been described that inflammation contributes to increasing hepcidin in CKD patients 16,48 . However, a possible explanation for the absence of reduced hepcidin concentration in the current study could be the specific population studies based on age and presence of residual renal function, unsimilar to previous studies. ...
Anemia is a common complication that is associated with mortality in patients with chronic kidney disease (CKD). Despite the use of erythropoiesis-stimulating agents (ESAs) to correct anemia, some patients are hyporesponsive due to the state of micro-inflammation caused by uremic toxins and hepcidin, a hormone that plays a central role in iron homeostasis. Hemodiafiltration (OL-HDF) has been associated with better clearance of uremic toxins, such as indoxyl sulfate (IS), p-cresyl sulfate (PCS) and indole acetic ascorbic (IAA) than conventional hemodialysis (HD). The aim of the study was to evaluate the effect of OL-HDF treatment on the concentration of IS, PCS, IAA, hepcidin and inflammatory biomarkers in CKD patients. Thirty-one patients (> 65 years old) incident in OL-HDF were followed for 6 months. IS, PCS, IAA, biochemical parameters, hepcidin and inflammatory cytokines were evaluated at baseline and after 6 months. We observed a significant decrease in IS and CRP plasma concentration, an increase in hemoglobin and hematocrit after 6 months of treatment with OL-HDF (p <0.05). This prospective observational study demonstrated that OL-HDF was capable to reduce IS and CRP in older patients. Whether this reduction may have an impact on clinical outcomes must be investigated in a future study.
... Following previous discussions, it is known that Hepcidin is usually synthesized by hepatocytes and secreted into the bloodstream, which can regulate the delivery of iron into the circulation from macrophages, duodenal enterocytes, and hepatocytes [52]. Some studies have also confirmed that it can improve the iron status of sows [30], broilers [38], weaned piglets [25], cows [42]. ...
Using female Sprague–Dawley (SD) rats as a model, the current study aimed to investigate whether feeding 5-aminolevulinic acid (5-ALA) to female SD rats during gestation and lactation can affect the iron status of weaned rats and provide new ideas for the iron supplementation of piglets. A total of 27 pregnant SD rats were randomly assigned to three treatments in nine replicates, with one rat per litter. Dietary treatments were basal diet (CON), CON + 50 mg/kg 5-ALA (5-ALA50), and CON + 100 mg/kg 5-ALA (5-ALA100). After parturition, ten pups in each litter (a total of 270) were selected for continued feeding by their corresponding mother, and the pregnant rats were fed diets containing 5-ALA (0, 50 and 100 mg/kg diet) until the newborn pups were weaned at 21 days. The results showed that the number of red blood cells (RBCs) in weaned rats in the 5-ALA100 group was significantly higher (p < 0.05) than that in the CON or 5-ALA50 group. The diet with 5-ALA significantly increased (p < 0.05) the hemoglobin (HGB) concentration, hematocrit (HCT) level, serum iron (SI) content, and transferrin saturation (TSAT) level in the blood of weaned rats, as well as the concentration of Hepcidin in the liver and serum of weaned rats and the expression of Hepcidin mRNA in the liver of weaned rats, with the 5-ALA100 group having the highest (p < 0.05) HGB concentration in the weaned rats, and the 5-ALA50 group having the highest (p < 0.05) Hepcidin concentration in serum and in the expression of Hepcidin mRNA in the liver of weaned rats. The other indicators between the 5-ALA groups had no effects. However, the level of total iron binding capacity (TIBC) was significantly decreased (p < 0.05) in the 5-ALA50 group. Moreover, the iron content in the liver of weaned rats fed with 5-ALA showed an upward trend (p = 0.085). In addition, feeding a 5-ALA-supplemented diet could also significantly reduce (p < 0.05) the expression of TfR1 mRNA in the liver of weaning rats (p < 0.05), and the expression of Tfr1 was not affected between 5-ALA groups. In conclusion, dietary supplementation with 5-ALA could improve the blood parameters, increase the concentration of Hepcidin in the liver and serum, and affect the expression of iron-related genes in the liver of weaned rats. Moreover, it is appropriate to add 50 mg/kg 5-ALA to the diet under this condition.
... This is the only portion of iron absorbed. On the basolateral outer surface, the ferroxidase hephaestin re-oxidizes Fe 2+ into Fe 3+ , which is the only iron form capable of binding transferrin and be finally taken into circulation [27] (Table 1 A key regulating role is played by the peptide hepcidin (for an exhaustive review, see [28]). When the liver detects an excess of the transferrin-bound iron, it responds by increasing the synthesis of hepcidin, which binds to ferroportin on the enterocytes' basolateral surface, causing its internalization into the cell, where ferroportin is rapidly degraded [29]. ...
Reactive Oxygen Species (ROS) play a key role in the neurodegeneration processes. Increased oxidative stress damages lipids, proteins, and nucleic acids in brain tissue, and it is tied to the loss of biometal homeostasis. For this reason, attention has been focused on transition metals involved in several biochemical reactions producing ROS. Even though a bulk of evidence has uncovered the role of metals in the generation of the toxic pathways at the base of Alzheimer’s disease (AD), this matter has been sidelined by the advent of the Amyloid Cascade Hypothesis. However, the link between metals and AD has been investigated in the last two decades, focusing on their local accumulation in brain areas known to be critical for AD. Recent evidence revealed a relation between iron and AD, particularly in relation to its capacity to increase the risk of the disease through ferroptosis. In this review, we briefly summarize the major points characterizing the function of iron in our body and highlight why, even though it is essential for our life, we have to monitor its dysfunction, particularly if we want to control our risk of AD.
... Appropriately, the expansion of the erythroid precursor population, such Nemeth as after bleeding or administration of erythropoietin, suppresses hepcidin through a mediator released by the bone marrow. Studies during the last decade have identified erythroferrone as a key erythroid factor mediating the suppression of hepcidin in response to bleeding or exogenous erythropoietin (5). The homeostatic mechanism can become pathological in diseases with ineffective erythropoiesis, where erythrocyte precursors massively expand but undergo apoptosis rather than maturing into erythrocytes. ...
Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.
Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... IL-6 and IL-1β, as well as LPS, are potent inducers of the master regulator of iron homeostasis, hepcidin (80). Hepcidin is produced by the liver and binds to the membrane protein ferroportin, an iron-efflux channel on the surface of all cells, inducing its internalization and degradation in lysosomes, thereby sequestering iron in the cytoplasm and decreasing plasma iron (81). Ferroportin is also expressed in skeletal muscle, but its role in iron transport in muscle has received little attention. ...
Sarcopenia is an age-related condition of slow, progressive loss of muscle mass and strength, which contributes to frailty, increased risk of hospitalisation and mortality, and increased health care costs. The incidence of sarcopenia is predicted to increase to >200 million affected older adults worldwide over the next 40 years, highlighting the urgency for understanding biological mechanisms and developing effective interventions. An understanding of the mechanisms underlying sarcopenia remains incomplete. Iron in the muscle is important for various metabolic functions including oxygen supply and electron transfer during energy production, yet these same chemical properties of iron may be deleterious to the muscle when either in excess or when biochemically unshackled (e.g., in ferroptosis), it can promote oxidative stress and induce inflammation. This review outlines the mechanisms leading to iron overload in muscle with aging and evaluates the evidence for the iron overload hypothesis of sarcopenia. Based on current evidence, studies are needed to: 1) determine the mechanisms leading to iron overload in skeletal muscle during aging; and 2) investigate whether skeletal muscles are functionally deficient in iron during aging leading to impairments in oxidative metabolism.
... This response likely evolved as part of nutritional immunity to prevent increased virulence of bloodborne pathogens utilizing iron in the blood (20). If persistent, a consequence of nutritional immunity may be declines in iron status and restriction of iron from erythropoiesis, such as with anemia of inflammation or anemia of chronic disease (21). ...
Background
Declines in iron status are frequently reported in those who regularly engage in strenuous physical activity. A possible reason for the declines in iron status with physical activity is increases in the iron regulatory hormone hepcidin, which functions to inhibit dietary iron absorption and can be induced by the inflammatory cytokine interleukin-6 (IL-6).
Objective
The current study aimed to determine the impact of a prolonged bout of running on hepcidin and dietary iron absorption in trained female and male runners.
Methods
Trained female and male collegiate cross country runners (n=28; age: 19.7±1.2 y; VO2max: 66.1±6.1 mL‧kg–1‧min–2; serum ferritin: 21.9±13.3 ng/mL) performed a prolonged run (98.8±14.7 min, 21.2±3.8 km, 4.7±0.3 min/km) during a team practice. Participants consumed a stable iron isotope with a standardized meal 2 h post-run and blood was collected 1 h later. The protocol was repeated 2 weeks later except participants abstained from exercise (rest). Red blood cells were collected 15 d after exercise and rest to determine isotope enrichment. Differences between exercise and rest were assessed by paired t-tests and Wilcoxon matched-pairs signed rank tests. Data are means±SD.
Results
Plasma hepcidin increased 52% after exercise (45.8±34.4 ng/mL) compared to rest (30.3±27.2 ng/mL, P=0.0011). Fractional iron absorption was reduced by 36% after exercise (11.8±14.6%) compared to rest (18.5±14.4%, P=0.025). Plasma IL-6 was greater after exercise (0.660±0.354 pg/mL) compared to rest (0.457±0.212 pg/mL, P<0.0001). Exploratory analyses revealed that the increase in hepcidin with exercise may be driven by a response in males but not females.
Conclusions
A prolonged bout of running increases hepcidin and decreases dietary iron absorption compared to rest in trained runners with low iron stores. The current study supports that IL-6 contributes to the increase in hepcidin with prolonged physical activity, though future studies should explore potential sex differences in the hepcidin response.
... Ferroportin is the main target of hepcidin. When bound to hepcidin, it prevents iron transport from the in- testinal epithelium and release from the reticuloendothelial cell system, ultimately leading to anemia [16,17]. Hemoglobin (Hb) content, as well as red blood cell counts, are largely reduced, with a mean Hb level of 94.57 ± 25.90 g/L in the case group, which is significantly lower than that in the healthy subjects (p < 0.05). ...
Background:
The goal of this study is to explore the clinical value of routine tests in multiple myeloma (MM).
Methods:
A total of 179 MM patients, newly diagnosed in our hospital from January 2010 to December 2018 (case group), as well as 352 cases of healthy individuals (control group) were evaluated. Albumin (Alb), globulin (Glb), albumin/globulin (A/G), creatinine (Cr), calcium (Ca), hemoglobin (Hb), lactate dehydrogenase (LDH), platelet count (Plt), and platelet distribution width (PDW) were compared between the analyzed groups. Respective tests were screened by forward selection. Thereafter, screened out indicators were identified through logistic regression analysis. Risk prediction nomogram, area under curve (AUC), calibration, decision curve analysis (DCA), and clinical impact curve (CIC) were further performed. At the same time, routine test indicators of MM patients for stage and subtype diagnosis, were compared. A correlation analysis between these test indicators and respective disease stages was performed. High stage group and low stage groups were subsequently compared to define the predictive value of single and combined indicators of disease severity.
Results:
Except for Ca, the difference between the case and control groups for all other blood indicators was statistically significant (p < 0.05). Moreover, the difference in positive rate(s) was statistically significant (p < 0.05). The receiver operating characteristic (ROC) curve of Alb, Hb, and PDW harbored robust discrimination (AUC = 0.960) and appropriate calibration. The DCA and CIC showed that the resulting nomogram had a superior net benefit in predicting MM. Among all indicators, only LDH was statistically reduced in MM patients at ISS stages I, II, and III (p < 0.05). Interestingly, the ISS stage of respective MM patients was positively correlated with Cr (τ = 0.392), while it was negatively correlated with Hb (τ = -0.364). Alb, Glo, A/G, and Hb were significantly distinct between heavy chain (IgG, IgA) and LC, while few significant differences were found between the ISS stages. Lastly, the AUC (0.828) for Cr was greater than that for all other single and combined indicators.
Conclusions:
The effective application of major indicators measured in routine blood tests can provide important clues for the diagnosis and prognosis of MM.
... Inflammatory signals, but not the infection itself, trigger changes in stem cell quiescence, self-renewal, and differentiation. Chronic inflammation drives sustained anemia based on inflammatory cytokines throughout the body, affecting macrophages in the bone marrow [44][45][46][47] . MDS also constitutes a condition associated with cytopenia, particularly in anemia, in which hematopoietic stem and progenitor cells acquire a mutation that leads to a clonal expansion of immature cells; additionally, in the bone marrow, variable grades of dysplasia are present, with various degrees of cytopenia [48] . ...
Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems, thought to properly sustain blood cell production and distinguish between friend and foe, can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state. The bone marrow niche hijacks the physiologic hematopoiesis. The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence. We examined several approaches to confront the available evidence; three key points emerged, pointing to the chronic inflammation process, especially the chronic infection and systemic inflammatory states, as leading causes of hematopoietic stem cell depletion. Clonal hematopoiesis, defined as a relative expansion of individual clones, is caused by somatic alterations in essential hematopoietic genes, which increase stem cell fitness. Moreover, terminal differentiation plays a significant role in progenitor loss and inflammatory signaling, promoting clonal selection and clonal hematopoiesis conditions. Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation, including the 5q-syndrome, Philadelphia negative myeloproliferative neoplasms, and chronic myeloid leukemia. Aging with increased fitness and hematopoietic stem cell attrition, extrinsic stress, enhanced stressor-specific fitness, and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis. The discussion in this review also points out that the hematopoietic niches' inflammatory stimulation may affect differentiation patterns and the function of downstream cells.
... Haemoglobin and myoglobin predominantly, but a signicant level of it is metabolized for various oxidative and reduction reactions. Being multivalent, Iron accepts and donates [4,5,6] electrons amid conversion from ferric and ferrous oxidative states. This homeostasis of iron to ensure adequate supply and prevention of [7] its excess or overload in the body is crucial thus. ...
BACKGROUND AND OBJECTIVE: Breasts are an important aspect of a woman's femininity and all aberrations in their functional and cosmetic attributes are essential for scientic evaluation as breast cancer has become the most common cancer among women worldwide. Its risk increases with age and menopausal status. Serum parameters like Ferritin and TIBC concentration is altered in sera of these patients. Iron homeostasis is inuenced by estrogen and overload impacts cellular proliferation and physiological dysfunction in electron and oxygen transport, energy production and DNA synthesis. A vicious cycle between breast cancer, iron homeostasis deregulation, menopausal status and serum parameters derangement enables us to prognosticate such patients. METHOD: Histopathologically conrmed, 50 newly diagnosed cases were analyzed with age matched 50 clinically healthy controls with no family history. Level of serum ferritin was estimated by Sandwich Elisa using Ferritin SAElisa kit and serum TIBC level measured with CL-1000i Chemiluminescence immunoassay analyzer. RESULT: Serum ferritin level in breast cancer cases (300.73±25.33ng/ml) was statistically higher than in controls (85.22±41.80ng/ml). In breast cancer, ferritin level was higher in postmenopausal (300.73±25.33ng/ml) compared to premenopausal (228.059±11.24ng/ml) patients and even in their healthy counterparts.Serum TIBC level in breast cancer (772.99±127.93) was higher than in controls (329.41± 69.40).In postmenopausal breast cancer female TIBC level was higher (815.39±104.32) compared to premenopausal females (652.31±110.86) and similarly it was higher in postmenopausal healthy controls than in premenopausal controls and signicant statistically. CONCLUSION: Serum ferritin and TIBC parameters can be used as prognostic markers for breast cancer and their levels are elevated in postmenopausal females of both breast cancer patients and healthy cases.
... The hormone, hepcidin, is a negative regulator of iron metabolism, and binds to FPN, inducing its internalization and degradation, and is involved in pathological regulation of iron in response to infection, inflammation, hypoxia, and anemia (59). Hepcidin controls the absorption of dietary iron as well as the distribution of iron between intracellular stores and extracellular fluids, including plasma (60). HO-1 contribution to iron homeostasis has been postulated. ...
Iron metabolism is vital for the survival of both humans and microorganisms. Heme oxygenase-1 (HO-1) is an essential stress-response enzyme highly expressed in the lungs, and catabolizes heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV)/bilirubin (BR), especially in pathological conditions which cause oxidative stress and inflammation. Ferrous iron (Fe ²⁺ ) is an important raw material for the synthesis of hemoglobin in red blood cells, and patients with iron deficiency are often associated with decreased cellular immunity. CO and BR can inhibit oxidative stress and inflammation. Thus, HO-1 is regarded as a cytoprotective molecule during the infection process. However, recent study has unveiled new information regarding HO-1. Being a highly infectious pathogenic bacterium, Mycobacterium tuberculosis (MTB) infection causes acute oxidative stress, and increases the expression of HO-1, which may in turn facilitate MTB survival and growth due to increased iron availability. Moreover, in severe cases of MTB infection, excessive reactive oxygen species (ROS) and free iron (Fe ²⁺ ) due to high levels of HO-1 can lead to lipid peroxidation and ferroptosis, which may promote further MTB dissemination from cells undergoing ferroptosis. Therefore, it is important to understand and illustrate the dual role of HO-1 in tuberculosis. Herein, we critically review the interplay among HO-1, tuberculosis, and the host, thus paving the way for development of potential strategies for modulating HO-1 and iron metabolism.
... When hepcidin is downregulated, intestinal iron absorption and iron release by macrophages is enhanced, resulting in iron overload. [11][12][13][14][15][16][17][18][19][20][21] The excess of absorbed iron is in part utilized for erythropoiesis, but the increased number of erythroid precursors typical of MDS is not able to fully utilize iron, which accumulates as non-transferrinbound iron (NTBI) and causes organ damage. Ultimately, iron overload is maintained by hepcidin inhibition mediated by enhanced bone marrow proliferation and iron is inadequately used due to ineffective erythropoiesis and defective red blood cell (RBC) maturation. ...
Sarah Parisi,1 Carlo Finelli2 1IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy; 2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, ItalyCorrespondence: Sarah Parisi Email sarah.parisi2@unibo.itAbstract: Iron chelation therapy (ICT) is an important tool in the treatment of transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients. ICT is effective in decreasing iron overload and consequently in limiting its detrimental effects on several organs, such as the heart, liver, and endocrine glands. Besides this effect, ICT also proved to be effective in improving peripheral cytopenia in a significant number of MDS patients, thus further increasing the clinical interest of this therapeutic tool. In the first part of the review, we will analyze the toxic effect of iron overload and its mechanism. Subsequently, we will revise the clinical role of ICT in various subsets of MDS patients (low, intermediate, and high risk MDS, patients who are candidates for allogeneic stem cell transplantation).Keywords: iron overload, myelodysplastic syndrome, iron chelation therapy, hepcidin
... 15 In this regard, the recent study has shown that excess extracellular labile irons may reduce the therapeutic effect of VC. 16 While the cell culture medium used in in vitro experiments generally has a low iron content (about 2−5 μM labile iron), 17 iron concentration in plasma is roughly 10−30 μM. 18 Such excess extracellular labile irons decompose the VC-induced H 2 O 2 through extracellular Fenton reaction before it penetrates into the cell (Figure 1d). 16 Although the products of Fenton reaction ( • OH and OH − ) are well-known reactive oxygen species (ROS) causing a strong cytotoxic effect, especially in the intracellular region due to the strong reactivity, 12,19 those produced in the extracellular region are inactivated before reaching the tumor cells 20 and cannot exert oxidative damage on them. ...
... Iron (Fe) is an essential trace element required in numerous important biological processes of animals (Hansen et al., 2009;Ganz and Nemeth, 2011). Rapidly growing chicks have a high demand for Fe (Ma et al., 2016), so Fe additives are routinely supplemented into diets for optimal growth. ...
No information is available regarding the utilization of iron (Fe) from different Fe sources at a target tissue level. To detect differences in Fe metabolic utilization among Fe sources, the effect of intravenously injected Fe on growth performance, hematological indices, tissue Fe concentrations and Fe-containing enzyme activities and gene expressions of Fe-containing enzymes or protein in broilers was investigated. On d 22 post-hatching, a total of 432 male chickens were randomly allotted to 1 of 9 treatments in a completely randomized design. Chickens were injected with either a 0.9% (wt/vol) NaCl solution (control) or a 0.9% NaCl solution supplemented with Fe sulphate or 1 of 3 organic Fe sources. The 3 organic Fe sources were Fe chelates with weak (Fe-MetW), moderate (Fe-ProM) or extremely strong (Fe-ProES) chelation strengths. The 2 Fe dosages were calculated according to the Fe absorbabilities of 10% and 20% every 2 d for a duration of 20 d. Iron injection did not affect (P > 0.05) ADFI, ADG or FCR during either 1 to 10 d or 11 to 20 d after injections. Hematocrit and Fe concentrations in the liver and kidney on d 10 after Fe injections, and Fe concentrations in the liver or pancreas and ferritin heavy-chain (FTH1) protein expression level in the liver or spleen on d 20 after Fe injections increased (P ≤ 0.05) as injected Fe dosages increased. When the injected Fe level was high at 20% Fe absorbability, the chickens injected with Fe-ProtES had lower (P < 0.001) kidney Fe concentrations and spleen FTH1 protein levels than those injected with Fe-MetW on d 20 after injections. And they had lower (P < 0.02) liver cytochrome c oxidase mRNA levels on d 20 after injections than those injected with Fe-Prot W or Fe sulphate. The results from this study indicate that intravenously injected Fe from Fe-ProES was the least utilizable and functioned in the sensitive target tissue less effectively than Fe from Fe sulfate, Fe-MetW or Fe-ProM.
... Maintaining proper iron concentration in our body is of great significance because iron, in forms of heme, iron-sulfur cluster (Fe-S), or iron itself as important cofactors, is involved in multiple biochemical pathways, including hemoglobin (HGB) synthesis and mitochondrial respiratory chain (Hentze et al., 2004;Darshan et al., 2010;Ganz and Nemeth, 2012;Rouault, 2013). For this reason, mammals have developed sophisticated mechanisms to maintain proper iron concentration in the body: (1) systemic iron homeostasis is maintained by hepcidin-ferroportin (hepcidin-FPN1, encoded by HAMP and SCL40A1) axis (Nemeth et al., 2004;Ganz and Nemeth, 2011) and (2) cellular iron homeostasis is mediated by iron regulatory proteins [IRPs, IRP1, and iron regulatory protein 2 (IRP2), also called ACO1 and iron-responsive element-binding protein 2 (IREB2)] through IRP-iron responsive element (IRE) system (Rouault, 2006;Wallander et al., 2006;Muckenthaler et al., 2008;Rouault, 2013). More tissue-specific strategies have also been developed, e.g., ferritinophagy to regulate erythropoiesis (Mancias et al., 2015). ...
Iron regulatory protein 2 (IRP2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1α and Hif2α expression; inhibition of Hif2α rescues Irp2 ablation-induced mitochondrial dysfunction; and inhibition of Hif1α suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1α and Hif2α are also elevated in vivo and play a similar role in neurological disorder of Irp2–/– mice. In this study, we confirmed the upregulation of Hif2α, not Hif1α, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of Irp2–/– mice. Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo but also suppressed glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) was reversed. Our results indicate that Irp2 depletion-induced Hif2α is, in vivo, in charge of the switch between OXPHOS and glycolysis, suggesting that, for the first time to our knowledge, Hif2α is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome.
... The cytokine IL-6 induces hepatic synthesis of hepcidin, which regulates iron homeostasis by controlling the degradation of the iron export protein ferroportin-1, which prevents iron absorption from the small intestine and release of iron from macrophages. Iron is therefore unavailable for erythropoiesis [34]. In addition to cytokine production, cancer itself can cause anemia by suppressing hematopoiesis through bone marrow infiltration. ...
Anemia is a common complication of cancer. Treatment of anemia in cancer is crucial as anemia adversely affects the quality of life, therapeutic outcomes, and overall survival. Erythropoiesis stimulating agents (ESAs) are valuable drugs for treating cancer-related anemia. Cardiovascular adverse effects are a significant concern with ESA therapy, and there is wide variability in therapeutic goals and characteristics of patients who undergo treatment with ESAs. As a result, a careful analysis of the currently available data on the efficacy and safety of these drugs is necessary. This data analysis will aid in the rational use of ESAs for the treatment of anemia in cancer. The objective of this systematic review is to elucidate the pathogenesis of anemia in cancer, assess the effectiveness of ESAs in treating anemia in cancer, and the overall risk of cardiovascular adverse effects associated with the use of ESAs and their impact on prognosis.
We searched literature from online databases - PubMed, PubMed Central, MEDLINE, Cochrane Library, and clinical trials register (clinicaltrials.gov) to identify prospective phase II and phase III randomized controlled trials (RCTs). We chose RCTs that directly compared patients with cancer who were treated with ESAs to those who were not treated with ESAs. January 2008 was taken as the lower date limit and May 2021 as the upper date limit. Only English language literature and human studies were included. The quality appraisal was completed using the Cochrane risk bias assessment tool, and data from a total of 10,738 patients with cancer in 17 RCTs were identified and included for systematic review.
Our review concludes that ESAs effectively reduce the necessity for blood transfusions and increase mean hemoglobin levels in anemic cancer patients. ESA therapy is associated with cardiovascular adverse effects, including venous thromboembolism, thrombophlebitis, hypertension, ischemic heart disease, cardiac failure, arrhythmia, arterial thromboembolism, and cardiac arrest. Aggressive ESA dosing to achieve higher hemoglobin levels and preexisting uncontrolled hypertension increases these cardiovascular side effects. Venous thromboembolism is the most significant adverse effect attributed to ESA therapy. However, there is no major change in overall survival with ESA therapy, and administration of ESAs can be carried out in anemic cancer patients with careful assessment of thromboembolism risk factors, risk-benefit ratio, and monitoring of hemoglobin levels.
... But unfortunately, there were not any laboratory experiments evidence conducted in RCC. HAMP is famous for the maintenance of iron homeostasis 57,58 and the regulation of cell growth and cycle. 59 Studies have showed iron metabolism was correlated with inflammation 60 and malignant tumor, such as multiple myeloma, 61 hepatocellular carcinoma, 62 and renal carcinoma. ...
Background
Renal cell carcinoma (RCC) contributed to 403,262 new cases worldwide in 2018, which constitutes 2.2% of global cancer, nevertheless, sunitinib, one of the major targeted therapeutic agent for RCC, often developed invalid due to resistance. Emerging evidences suggested sunitinib can impact tumor environment which has been proven to be a vital factor for tumor progression.
Methods
In the present study, we used ssGSEA to extract the immune infiltrating abundance of clear cell RCC (ccRCC) and normal control samples from GSE65615, TCGA, and GTEx; key immune cells were determined by Student's t-test and univariable Cox analysis. Co-expression network combined with differentially expressed analysis was then applied to derive key immune-related genes for ccRCC, followed by the identification of hub genes using differential expression analysis. Subsequently, explorations and validations of the biological function and the immune-related and sunitinib-related characteristics were conducted in KEGG, TISIDB, Oncomine, ICGC, and GEO databases.
Results
We refined immature dendritic cells and central memory CD4 T cells which showed associations with sunitinib and ccRCC. Following, five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) were identified for their strong relationships with sunitinib and immune infiltration in ccRCC. Further validations in external data refined CRYBB1, CEACAM4, and HAMP which play a vital role in sunitinib resistance, immune infiltrations in ccRCC, and the development and progression of ccRCC. In conclusion, our findings could shed light on the resistance of sunitinib in ccRCC and provide novel biomarkers or drug targets for ccRCC.
... TIBC was lower in the study group (50.4 µmol/L) than in the control group (66.0 µmol/L). This is explained by that in patients with CKD anemia is a common comorbidity and contribute to many factors as CKD progresses, including impaired production of erythropoietin (16) , and hepcidin-mediated iron restriction (17) . Also, iron deficiency plays an important role in pathogenesis of anemia in CKD patients (18) . ...
This chapter explores the multiplicities and entanglements of health and disease at Arroyo Hondo Pueblo. Interpreting patterns of pathology for past groups depends on how multiple conceptual frameworks emphasize some issues while hiding others. At Arroyo Hondo, sustenance frames how food practices, diet, and human physiology were entangled with spaces, things, other species, and beliefs. De-centering the body emphasizes its trans-corporeal relationships as a holobiont. How disease states emerged at this fourteenth century Ancestral Puebloan village reflect the entangled pathogenicity of micronutrient deficiencies, infections, parasites, and mycotoxins. I also discuss how notions of disease ecologies and pathological lives articulate disease states as immersed experiences.
Dysmetabolic iron overload syndrome (DIOS) defines a moderate increase in body iron load in the absence of an identifiable cause of iron excess, and one of its main target organs is the liver. DIOS has been reported to be associated with hyperferritinemia, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and atherosclerotic heart disease. Despite iron overload, hepcidin overexpression has been reported in patients with DIOS. However, underlying mechanisms for impaired hepcidin function have not been illuminated yet. Nuclear receptor coactivator 4 (NCOA4) plays a significant role in intracellular iron traffic by regulating cellular iron levels as being the rate-limiting factor for ferritinophagy. Functional studies on NCOA4 have revealed that loss of NCOA4 function causes ferritin accumulation in every tissue examined. Here, we hypothesized that some of the patients with NAFLD develop DIOS, because of dysmetabolic overexpression of hepcidin that inhibits NCOA4 expression, leading to ferritin accumulation within hepatocytes, but not reticuloendothelial cells of the liver.
Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6-/- mice revealed that increases in the dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct the iron-deficiency anemia. Interestingly, the increased iron in Tmprss6-/- mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.
The injury caused by ischemia and subsequent reperfusion (I/R) is inevitable during kidney transplantation and its current management remains unsatisfactory. Iron is considered to play a remarkable pathologic role in the initiation or progression of tissue damage induced by I/R, whereas the effects of iron-related therapy remain controversial owing to the complicated nature of iron's involvement in multiple biological processes. A significant portion of the cellular iron is located in the mitochondria, which exerts a central role in the development and progression of I/R injury. Recent studies of iron regulation associated with mitochondrial function represents a unique opportunity to improve our knowledge on the pathophysiology of I/R injury. However, the molecular mechanisms linking mitochondria to the iron homeostasis remain unclear. In this review, we provide a comprehensive analysis of the alterations to iron metabolism in I/R injury during kidney transplantation, analyze the current understanding of mitochondrial regulation of iron homeostasis and discussed its potential application in I/R injury. The elucidation of regulatory mechanisms regulating mitochondrial iron homeostasis will offer valuable insights into potential therapeutic targets for alleviating I/R injury with the ultimate aim of improving kidney graft outcomes, with potential implications that could also extend to acute kidney injury or other I/R injuries.
Anaemia is common in chronic kidney disease (CKD). Iron deficiency and erythropoietin deficiency are perhaps the most common causes of anaemia in patients with CKD, especially those requiring kidney replacement therapy (KRT/dialysis) (Centers for Disease Control and Prevention, https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html, 2019; The National Collaborating Centre for Chronic Kidney Disease: National Institute for Health and Clinical Excellence: Guidance. In: Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care, eds. Royal College of Physicians (UK). Royal College of Physicians of London, London, 2008; UK Renal Registry, UK renal registry 22nd annual report—data to 31/12/2018, Bristol; 2020. renal.org/audit-research/annual-report). The Renal National Service Framework and National Institute for Health and Clinical Excellence in the UK, and Kidney Disease Improving Global Outcomes (KDIGO), all advocate treatment of anaemia in patients with CKD (Locatelli et al., Kidney Int 74:1237–1240, 2008; Mikhail et al., BMC Nephrol 18:345, 2017; Locatelli et al., Nephrol Dial Transplant 28:1346–1359, 2013; National Clinical Guideline Centre: National Institute for Health and Care Excellence (NICE). Anaemia management in chronic kidney disease NG8. 2015. https://www.nice.org.uk/guidance/ng8/evidence/full-guideline-pdf-70545136). Intravenous (IV) Iron therapy leads to a reduction in the use of erythropoietin stimulating agents (ESA). This reduction in ESA use may be potentially beneficial in certain cases such as reducing cardiovascular risk. Also, the close relationship of anaemia, iron deficiency, CKD and cardiovascular disease make its therapy critical to improved clinical outcomes (De Silva et al., Am J Cardiol 98:391–398, 2006). ESA therapy remains important after iron repletion to optimise haemoglobin concentrations to a KDIGO target range of 100–115 g/L (Locatelli et al., Kidney Int 74:1237–1240, 2008; Locatelli et al., Nephrol Dial Transplant 28:1346–1359, 2013). Blood transfusions are infrequently required, and newer therapies such as Hypoxia-inducible factor (HIF) stabilisers are on the horizon (Besarab et al., Nephrol Dial Transplant 30:1665–1673, 2015; Singh et al., N Engl J Med 385:2313–24, 2021; Singh et al., N Engl J Med 385:2325–35, 2021).KeywordsAnaemia in CKDDialysisNormocytic anaemiaErythropoietinEPOErythropoietin stimulating agentESAHIF stabilisersHepcidin
Anti-inflammation has become pivotal in chemoprevention of inflammatory bowel disease (IBD)-associated colorectal cancer (CRC). The chemopreventive effects of anti-inflammatory drugs currently used in IBD therapy are still not clear based on existing epidemiological studies. Therefore, novel chemopreventive candidates need to be investigated and natural products derived from food as well as complementary and alternative medicine have become attractive resources with advantages including multi-components and multi-targets. Danggui Decoction (DGD), composed of Angelicae Sinensis Radix, Zingiberis Recens Rhizoma and Jujubae Fructus, is a traditional Chinese medicinal formula for the treatment of IBD, and DGD supercritical fluid extracts (DGDSFE) as well as DGD polysaccharide extracts (DGDPE) are potential effective constituents for chemoprevention. This article constructed a multi-unit pellet drug delivery system (MUPDDS) containing two independent parts, DGDSFE colon-targeted pellets and DGDPE pellets, according to the different characteristics of extracts, by applying extrusion-spheronization and coating technology. The chemopreventive effect of this MUPDDS was evaluated in the rat model induced by 1,2-dimethylhydrazine and dextran sulfate sodium. The tumor incidence, tumor number and tumor volume were reduced after the administration of MUPDDS daily for 14 weeks, with serum levels of TNF-α, IL-1β and hepcidin decreased and levels of IFN-γ and IL-2 in splenocyte supernatant elevated, indicating anti-inflammation, iron metabolism regulation and immune regulation of DGDSFE and DGDPE in MUPDDS. Furthermore, the feasibility and advantage of MUPDDS in chemoprevention was displayed by compared with extracts, DGDSFE colon-targeted pellets or DGDPE pellets, providing an inspiring strategy to achieve better effect of traditional Chinese medicines in cancer prevention.
Understanding the key regulator of iron homeostasis is critical to the improvement of iron supplementation practices in malaria-endemic areas. This study aimed to determine iron indices and hepcidin (HEPC) level in patients infected with Plasmodium falciparum compared to apparently healthy, malaria-negative subjects in Hodeidah, Yemen. The study included 70 Plasmodium falciparum-infected and 20 malaria-negative adults. Blood films were examined for detection and estimation of parasitemia. Hemoglobin (Hb) level was measured using an automated hematology analyzer. Serum iron and total iron binding capacity (TIBC) were determined by spectrophotometric methods. Levels of serum ferritin (FER) and HEPC were measured by enzyme-linked immunosorbent assays. Data were stratified by sex and age. Comparable Hb levels were found in P. falciparum-infected patients and malaria-negative subjects in each sex and age group (p > 0.05). Compared to their malaria-negative counterparts, disturbed iron homeostasis in patients was evidenced by the significantly lower serum iron levels in females (p = 0.007) and those aged <25 years (p = 0.02) and the significantly higher TIBC in males (p = 0.008). Levels of serum FER and HEPC were significantly elevated in P. falciparum-infected patients compared to the corresponding malaria-negative participants (p < 0.001). Serum FER correlated positively with parasite density (p = 0.004). In conclusion, patients with uncomplicated P. falciparum in Hodeidah display elevated levels of serum HEPC and FER. Hemoglobin level may not reflect the disturbed iron homeostasis in these patients. The combined measurement of iron indices and HEPC provides comprehensive information on the iron status so that the right intervention can be chosen.
Early and adequate correction of the anemic syndrome (AS) of cancer patients can prevent deterioration in the quality of life and be considered as a reserve for increasing the effectiveness of treatment for breast cancer (BC). The aim of the study was to assess the status of iron using modern methods of ferrokinetics in breast cancer patients on the background of adjuvant chemotherapy for early diagnosis and adequate treatment of AS. The object of the study included 21 breast cancer patients with a relatively favorable prognosis, with luminal types A and B (Her 2 / neu positive or negative), three times negative type. The examination was carried out in the postoperative period, against the background of adjuvant chemotherapy. The main metabolites of ferrokinetics were studied: hepcidin 25 (GP25); ferritin (FR); soluble transferrin receptors (rRTP); transferin (TRF); iron (Fe); erythropoietin (EPO); CRP and IL-6 indicators. AC correction was performed (ferinject, epotin-alpha, B12). 10 (47.6%) patients with breast cancer had AS. Most of them were diagnosed with IDA with microcytic, hypochromic characteristics of erythrocytes, low concentration of FR, Fe, GP25, IL-6, CRP, and high levels of TRP and rRTP. Functional iron deficiency (FDF) was established in some patients. In contrast to patients with IDA, they had a high concentration of FR, CRP and significant production of GP25, IL-6. The EPO level was not optimal for the majority of patients with AS. In isolated cases, during treatment with recombinant erythropoietins, a deficiency of vitamin B12 (cyanocobalamin) was revealed. The rational use of iron preparations, vitamins, and recombinant forms of EPO made it possible to restore Fe metabolism, stabilize the hemoglobin level, and also improve the condition of most breast cancer patients. The obtained data on IL-6, GP25, CRP indicate a certain relationship between them in the development of anemia with VDF in breast cancer patients and the need for further study of the characteristics of iron metabolism in cancer patients.
Several lines of evidence suggest that estrogen (17-β estradiol; E2) protects against diabetes mellitus and plays important roles in pancreatic β-cell survival and function. Mounting clinical and experimental evidence also suggest that E2 modulates cellular iron metabolism by regulating the expression of several iron regulatory genes, including hepcidin (HAMP), hypoxia-inducible factor 1-α, ferroportin (SLC40A1), and lipocalin (LCN2). However, whether E2 regulates cellular iron metabolism in pancreatic β cells and whether the antidiabetic effects of E2 can be, at least partially, attributed to its role in iron metabolism is not known. In this context, pancreatic β cells express considerable levels of conventional E2 receptors (ERs; mainly ER-α) and nonconventional G protein-coupled estrogen receptors and hence responsive to E2 signals. Moreover, pancreatic islet cells require significant amounts of iron for proper functioning, replication and survival and, hence, well equipped to manage cellular iron metabolism (acquisition, utilization, storage, and release). In this review, we examine the link between E2 and cellular iron metabolism in pancreatic β cells and discuss the bearing of such a link on β-cell survival and function.
Hepcidin is a principal regulator of iron homeostasis and its dysregulation has been recognised as a causative factor in cancers and iron disorders. The strategy of manipulating the presence of hepcidin peptide has been used for cancer treatment. However, this has demonstrated poor efficiency and has been short-lived in patients. Many studies reported using minihepcidin therapy as an alternative way to treat hepcidin dysregulation, but this was only applied to non-cancer patients. Highly conserved fish hepcidin protein, HepTH1-5, was investigated to determine its potential use in developing a hepcidin replacement for human hepcidin (Hepc25) and as a therapeutic agent by targeting the tumour suppressor protein, p53, through structure-function analysis. The authors found that HepTH1-5 is stably bound to ferroportin, compared to Hepc25, by triggering the ferroportin internalisation via Lys42 and Lys270 ubiquitination, in a similar manner to the Hepc25 activity. Moreover, the residues Ile24 and Gly24, along with copper and zinc ligands, interacted with similar residues, Lys24 and Asp1 of Hepc25, respectively, showing that those molecules are crucial to the hepcidin replacement strategy. HepTH1-5 interacts with p53 and activates its function through phosphorylation. This finding shows that HepTH1-5 might be involved in the apoptosis signalling pathway upon a DNA damage response. This study will be very helpful for understanding the mechanism of the hepcidin replacement and providing insights into the HepTH1-5 peptide as a new target for hepcidin and cancer therapeutics.
Communicated by Ramaswamy H. Sarma
Background:
Thalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Beta-thalassemia is caused by one or more mutations in the beta-globin gene. The absence or reduced amount of beta-globin chains causes ineffective erythropoiesis which leads to anemia.
Methods:
Beta-thalassemia has been further divided into three main forms: thalassemia major, intermedia, and minor/silent carrier. A more severe form among these is thalassemia major in which individuals depend upon blood transfusion for survival. The high level of iron deposition occurs due to regular blood transfusion therapy.
Results:
Overloaded iron raises the synthesis of reactive oxygen species (ROS) that are noxious and prompting the injury to the hepatic, endocrine, and vascular system. Thalassemia can be analyzed and diagnosed via prenatal testing (genetic testing of amniotic fluid), blood smear, complete blood count, and DNA analysis (genetic testing). Treatment of thalassemia intermediate is symptomatic; however; it can also be accomplished by folic supplementation and splenectomy.
Conclusion:
Thalassemia major can be cured through regular transfusion of blood, transplantation of bone marrow, iron chelation management, hematopoietic stem cell transplantation, stimulation of fetal hemoglobin production, and gene therapy.
Despite advances in understanding the pathophysiology of acute kidney injury (AKI) and chronic kidney disease (CKD), treatment for kidney disease remains unsatisfactory. The labile iron pool consists of chemical forms that can participate in redox cycling and is therefore often referred to as catalytic iron. There are two broad lines of evidence for the role of labile iron in disease states: that it is increased in disease states and that iron chelators provide a protective effect, thus establishing a cause–effect relationship. We summarize the importance of labile iron in several models of AKI, including rhabdomyolysis, gentamicin, and cisplatin-induced AKI. In addition, we review evidence for the role of catalytic iron in inflammatory and noninflammatory models of experimental glomerular disease as well as models of progressive kidney disease. We finally provide some preliminary human data indicating that the extensive experimental observations in experimental models may be relevant to human disease. This focus on iron is particularly relevant because of the availability of iron chelators to potentially provide new therapeutic tools to prevent and/or treat kidney disease. Randomized clinical trials are needed to evaluate the safety and efficacy of iron chelators in the treatment of acute and CKD.
In the blood serum of 93 patients with various localities of the malignant process, the content of nitric oxide (NO), indicators of lipid peroxidation (POL): superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione in red blood cells were determined. 9 patients with ovarian cancer were examined during chemotherapy (6 courses), 40 patients with colon cancer, previously operated, were with malignant liver damage. In 39 patients with anemia, NO indicators were compared with the level of interleukin 6 (IL-6) and hepcidin-25 (GP-25). As a control, 60 practically healthy individuals were examined. It was shown that the NO content was significantly reduced in 69.7% of patients, regardless of the location of the primary tumor. There was a gradual increase in the NO content before each course of chemotherapy. A high concentration of NO (more than 22 µM) was detected in 22 patients with functional iron deficiency (FJ) against the background of anemia of chronic diseases (AHZ), which was accompanied by hyperexpression of IL-6 (27.0±10.5 pg/ml) and GP-25 (25.2±7.1 ng/ml). In contrast, the lowest NO values (less than 22 µM) were observed in 17 patients with IDA. There is no doubt that there is a certain relationship between the development of oxidative stress with the accumulation of highly toxic lipoperoxidation products that affect the overall homeostasis of the body, and the development of anemic syndrome.
Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling—dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6–stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.
Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma.
Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-alpha, and IL-1 beta were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay.
Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect.
These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.
Cytokines play a pivotal role in Hodgkin's lymphoma (HL). Because interleukin-6 (IL-6) induces expression of hepcidin, one of the principal regulators of iron metabolism, we studied the contribution of hepcidin in anemia in HL at diagnosis.
Plasma samples from 65 patients with HL were analyzed for hepcidin levels using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry; cytokine levels were analyzed using enzyme-linked immunosorbent assays and parameters of iron metabolism and acute-phase reaction.
Hepcidin plasma levels were significantly higher in HL patients when compared with controls, independent of the presence of anemia (P = .001). In the subset of patients with anemia, hepcidin levels inversely correlated with hemoglobin levels (P = .01). Analyzing parameters of iron metabolism, hepcidin levels showed a positive correlation with ferritin (P < .001) and an inverse correlation to iron and iron-binding capacity. Hepcidin strongly correlated to IL-6 levels (P < .001) but not to IL-10 or thymus and activation-regulated cytokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) levels. In a multivariate regression analysis, IL-6 and fibrinogen levels were independently associated with hepcidin. Higher hepcidin levels were observed in patients with more aggressive disease characteristics: stage IV disease (P = .01), presence of B symptoms (P = .03), and International Prognostic Score > 2 (P = .005).
Our findings suggest that in HL, hepcidin is upregulated by IL-6. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic inflammation, although hepcidin-independent mechanisms contribute to development of anemia in HL.
Hepcidin, the principal regulator of iron homeostasis, may play a critical role in the response of patients with anemia to iron and erythropoiesis-stimulating agent therapy; however, the contribution of hepcidin to iron maldistribution and anemia in hemodialysis (HD) patients and the ability of HD to lower serum hepcidin levels have not been fully characterized.
We measured serum hepcidin using a competitive ELISA in 30 pediatric and 33 adult HD patients. In addition, we determined serum hepcidin kinetics and calculated hepcidin clearance by measuring serum hepcidin before, during, and after HD in eight pediatric and six adult patients.
Hepcidin was significantly increased in pediatric (median 240.5 ng/ml) and adult HD patients (690.2 ng/ml) when compared with their respective control subjects (pediatric 25.3 ng/ml, adult 72.9 ng/ml). Multivariate regression analysis showed that serum hepcidin was independently predicted by ferritin and high-sensitivity C-reactive protein in the pediatric group and ferritin, percentage of iron saturation, and high-sensitivity C-reactive protein in the adult group. Hepcidin levels decreased after dialysis from 532 +/- 297 to 292 +/- 171 ng/ml. Hepcidin clearance by HD was 141 +/- 40 and 128 +/- 44 ml/min in pediatric and adult patients, respectively (NS).
These findings suggest that hepcidin may mediate the negative effects of inflammation on both disordered iron metabolism and erythropoiesis in HD patients and that intensification of HD could be used therapeutically to reduce hepcidin concentrations and thereby improve erythropoiesis-stimulating agent responsiveness.
Iron maldistribution has been implicated in multiple diseases, including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered, and thus, potentially contributes to AI. Human hepcidin (hHepc) overexpression in mice caused an iron-deficient phenotype, including stunted growth, hair loss, and iron-deficient erythropoiesis. It also caused resistance to supraphysiologic levels of erythropoiesis-stimulating agent, supporting the hypothesis that hepcidin may influence response to treatment in AI. To explore the role of hepcidin in inflammatory anemia, a mouse AI model was developed with heat-killed Brucella abortus treatment. Suppression of hepcidin mRNA was a successful anemia treatment in this model. High-affinity antibodies specific for hHepc were generated, and hHepc knock-in mice were produced to enable antibody testing. Antibody treatment neutralized hHepc in vitro and in vivo and facilitated anemia treatment in hHepc knock-in mice with AI. These data indicate that antihepcidin antibodies may be an effective treatment for patients with inflammatory anemia. The ability to manipulate iron metabolism in vivo may also allow investigation of the role of iron in a number of other pathologic conditions.
The recently discovered iron regulatory peptide hormone hepcidin holds promise as a novel biomarker in iron metabolism disorders. To date, various mass spectrometry and immunochemical methods have been developed for its quantification in plasma and urine. Differences in methodology and analytical performance hinder the comparability of data. As a first step towards method harmonization, several hepcidin assays were compared. Worldwide eight laboratories participated in a urinary and plasma round robin in which hepcidin was analyzed. For both urine and plasma: (i) the absolute hepcidin concentrations differed widely between methods, (ii) the between-sample variation and the analytical variation of the methods are similar. Importantly, the analytical variation as percentage of the total variance is low for all methods, indicating their suitability to distinguish hepcidin levels of different samples. Spearman correlations between methods were generally high. The round robin results inform the scientific and medical community on the status and agreement of the current hepcidin methods. Ongoing initiatives should facilitate standardization by exchanging calibrators and representative samples.
To date there have been few published immunoassays for the important iron regulator hepcidin. This study describes a novel competitive radioimmunoassay (RIA) for the bioactive hepcidin peptide. A rabbit anti-hepcidin polyclonal antibody was produced using synthetic hepcidin radiolabelled with 125I to produce a competitive RIA. Normal patient (n=47) samples were collected and assayed for hepcidin to determine a reference range. Other patient groups collected were ulcerative colitis (UC; n=40), iron deficiency anaemia (IDA; n=15), chronic kidney disease not requiring dialysis (CKD; n=45) and chronic kidney disease requiring dialysis (HCKD; n=94). Detection limit of the assay was determined as 0.6 ng/mL. Intra-assay precision was 5 ng/mL (7.2%) and 50 ng/mL (5.8%), interassay precision was 5 ng/mL (7.6%) and 50 ng/mL (6.7%). Analytical recovery was 98% (5 ng/mL), 94% (10 ng/mL) and 97% (50 ng/mL). The assay was linear up to 200 ng/mL. No demonstrable cross-reactivity with human insulin, glucagon I, angiotensinogen I, β-defensin 1-4, α-defensin-1 and plectasin was observed. There was significant correlation (r=0.96, P≤0.0001) between the hepcidin RIA and an established hepcidin SELDI-TOF-MS method. Analysis of the normal human samples gave a reference range of 1.1-55 ng/mL for hepcidin. Further statistical evaluation revealed a significant difference between male and female hepcidin levels. There was significant correlation between hepcidin and ferritin in the control group (r=0.6, P≤0.0001). There was also a significant difference between the normal and disease groups (P≤0.0001). Healthy volunteers (n=10) showed a diurnal increase in plasma hepcidin at 4.00 pm compared to 8.00 am. A robust and optimised immunoassay for bioactive hepcidin has been produced and the patient sample results obtained further validates the important role of hepcidin in iron regulation, and will allow further investigation of this important peptide and its role in iron homeostasis.
Hepcidin is a tightly folded 25-residue peptide hormone containing four disulfide bonds, which has been shown to act as the
principal regulator of iron homeostasis in vertebrates. We used multiple techniques to demonstrate a disulfide bonding pattern
for hepcidin different from that previously published. All techniques confirmed the following disulfide bond connectivity:
Cys1–Cys8, Cys3–Cys6, Cys2–Cys4, and Cys5–Cys7. NMR studies reveal a new model for hepcidin that, at ambient temperatures, interconverts between two different conformations,
which could be individually resolved by temperature variation. Using these methods, the solution structure of hepcidin was
determined at 325 and 253 K in supercooled water. X-ray analysis of a co-crystal with Fab appeared to stabilize a hepcidin
conformation similar to the high temperature NMR structure.
Ferroportin (FPN1), the sole characterized mammalian iron exporter, has an iron-responsive element (IRE) in its 5' untranslated region, which ensures that its translation is repressed by iron regulatory proteins (IRPs) in iron-deficient conditions to maintain cellular iron content. However, here we demonstrate that duodenal epithelial and erythroid precursor cells utilize an alternative upstream promoter to express a FPN1 transcript, FPN1B, which lacks the IRE and is not repressed in iron-deficient conditions. The FPN1B transcript encodes ferroportin with an identical open reading frame and contributes significantly to ferroportin protein expression in erythroid precursors and likely also in the duodenum of iron-starved animals. The identification of FPN1B reveals how FPN1 expression can bypass IRP-dependent repression in intestinal iron uptake, even when cells throughout the body are iron deficient. In erythroid precursor cells, we hypothesize that FPN1B expression enhances real-time sensing of systemic iron status and facilitates restriction of erythropoiesis in response to low systemic iron.
In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.
Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays.
This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2-4) and 32 adult (ACKD2-4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis.
When compared with their respective controls (pediatric median = 25.3 ng/ml, adult = 72.9 ng/ml), hepcidin was significantly increased in PCKD2-4 (127.3 ng/ml), ACKD2-4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2-4 (R(2) = 0.57), only ferritin correlated with hepcidin. In ACKD2-4 (R(2) = 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R(2) = 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R(2) = 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD.
These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.
The interaction between the hormone hepcidin and the iron exporter ferroportin (Fpn) regulates plasma iron concentrations. Hepcidin binds to Fpn and induces its internalization and degradation, resulting in decreased iron efflux from cells into plasma. Fpn mutations in N144, Y64N, and C326 residue cause autosomal dominant disease with parenchymal iron overload, apparently due to the resistance of mutant Fpn to hepcidin-mediated internalization. To define the mechanism of resistance, we generated human Fpn constructs bearing the pathogenic mutations. The mutants localized to the cell surface and exported iron normally, but were partially or completely resistant to hepcidin-mediated internalization and continued to export iron despite the presence of hepcidin. The primary defect with exofacial C326 substitutions was the loss of hepcidin binding, which resulted in the most severe phenotype. The thiol form of C326 was essential for interaction with hepcidin, suggesting that C326-SH homology is located in or near the binding site of hepcidin. In contrast, N144 and Y64 residues were not required for hepcidin binding, but their mutations impaired the subsequent internalization of the ligand-receptor complex. Our observations explain why the mutations in C326 Fpn residue produce a severe form of hemochromatosis with iron overload at an early age.
The anemia of chronic disease (ACD) is characterized by macrophage iron retention induced by cytokines and the master regulator hepcidin. Hepcidin controls cellular iron efflux on binding to the iron export protein ferroportin. Many patients, however, present with both ACD and iron deficiency anemia (ACD/IDA), the latter resulting from chronic blood loss. We used a rat model of ACD resulting from chronic arthritis and mimicked ACD/IDA by additional phlebotomy to define differing iron-regulatory pathways. Iron retention during inflammation occurs in macrophages and the spleen, but not in the liver. In rats and humans with ACD, serum hepcidin concentrations are elevated, which is paralleled by reduced duodenal and macrophage expression of ferroportin. Individuals with ACD/IDA have significantly lower hepcidin levels than ACD subjects, and ACD/IDA persons, in contrast to ACD subjects, were able to absorb dietary iron from the gut and to mobilize iron from macrophages. Circulating hepcidin levels affect iron traffic in ACD and ACD/IDA and are more responsive to the erythropoietic demands for iron than to inflammation. Hepcidin determination may aid to differentiate between ACD and ACD/IDA and in selecting appropriate therapy for these patients.
Expression of hepcidin, a key regulator of intestinal iron absorption, can be induced in vitro by several bone morphogenetic proteins (BMPs), including BMP2, BMP4 and BMP9 (refs. 1,2). However, in contrast to BMP6, expression of other BMPs is not regulated at the mRNA level by iron in vivo, and their relevance to iron homeostasis is unclear. We show here that targeted disruption of Bmp6 in mice causes a rapid and massive accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart and the renal convoluted tubules. Despite their severe iron overload, the livers of Bmp6-deficient mice have low levels of phosphorylated Smad1, Smad5 and Smad8, and these Smads are not significantly translocated to the nucleus. In addition, hepcidin synthesis is markedly reduced. This indicates that Bmp6 is critical for iron homeostasis and that it is functionally nonredundant with other members of the Bmp subfamily. Notably, Bmp6-deficient mice retain their capacity to induce hepcidin in response to inflammation. The iron burden in Bmp6 mutant mice is significantly greater than that in mice deficient in the gene associated with classical hemochromatosis (Hfe), suggesting that mutations in BMP6 might cause iron overload in humans with severe juvenile hemochromatosis for which the genetic basis has not yet been characterized.
Juvenile hemochromatosis is an iron-overload disorder caused by mutations in the genes encoding the major iron regulatory hormone hepcidin (HAMP) and hemojuvelin (HFE2). We have previously shown that hemojuvelin is a co-receptor for bone morphogenetic proteins (BMPs) and that BMP signals regulate hepcidin expression and iron metabolism. However, the endogenous BMP regulator(s) of hepcidin in vivo is unknown. Here we show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhibitor of BMP2 or BMP4 but a less potent inhibitor of BMP6 in vitro. In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepcidin expression and increases serum iron, whereas DRAGON.Fc has no effect. Notably, Bmp6-null mice have a phenotype resembling hereditary hemochromatosis, with reduced hepcidin expression and tissue iron overload. Finally, we demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidin expression and reduces serum iron in mice. These data support a key role for BMP6 as a ligand for hemojuvelin and an endogenous regulator of hepcidin expression and iron metabolism in vivo.
We developed and validated the first serum enzyme-linked immunosorbent assay for hepcidin, the principal iron-regulatory hormone that has been very difficult to measure. In healthy volunteers, the 5% to 95% range of hepcidin concentrations was 29 to 254 ng/mL in men (n = 65) and 17 to 286 ng/mL in women (n = 49), with median concentrations 112 versus 65 (P < .001). The lower limit of detection was 5 ng/mL. Serum hepcidin concentrations in 24 healthy subjects correlated well with their urinary hepcidin (r = 0.82). Serum hepcidin appropriately correlated with serum ferritin (r = 0.63), reflecting the regulation of both proteins by iron stores. Healthy volunteers showed a diurnal increase of serum hepcidin at noon and 8 pm compared with 8 am, and a transient rise of serum hepcidin in response to iron ingestion. Expected alterations in hepcidin levels were observed in a variety of clinical conditions associated with iron disturbances. Serum hepcidin concentrations were undetectable or low in patients with iron deficiency anemia (ferritin < 10 ng/mL), iron-depleted HFE hemochromatosis, and juvenile hemochromatosis. Serum hepcidin concentrations were high in patients with inflammation (C-reactive protein > 10 mg/dL), multiple myeloma, or chronic kidney disease. The new serum hepcidin enzyme-linked immunosorbent assay yields accurate and reproducible measurements that appropriately reflect physiologic, pathologic, and genetic influences, and is informative about the etiology of iron disorders.
Cysteine-rich antimicrobial peptides are abundant in animal and plant tissues involved in host defense. In insects, most are
synthesized in the fat body, an organ analogous to the liver of vertebrates. From human urine, we characterized a cysteine-rich
peptide with three forms differing by amino-terminal truncation, and we named it hepcidin (Hepc) because of its origin in
the liver and its antimicrobial properties. Two predominant forms, Hepc20 and Hepc25, contained 20 and 25 amino acid residues
with all 8 cysteines connected by intramolecular disulfide bonds. Reverse translation and search of the data bases found homologous
liver cDNAs in species from fish to human and a corresponding human genomic sequence on human chromosome 19. The full cDNA
by 5′ rapid amplification of cDNA ends was 0.4 kilobase pair, in agreement with hepcidin mRNA size on Northern blots. The
liver was the predominant site of mRNA expression. The encoded prepropeptide contains 84 amino acids, but only the 20–25-amino
acid processed forms were found in urine. Hepcidins exhibited antifungal activity against Candida albicans,Aspergillus fumigatus, and Aspergillus nigerand antibacterial activity against Escherichia coli,Staphylococcus aureus, Staphylococcus epidermidis, and group B Streptococcus. Hepcidin may be a vertebrate counterpart of cysteine-rich antimicrobial peptides produced in the fat body of insects.
We previously reported the disruption of the murine gene encoding the transcription factor USF2 and its consequences on glucose-dependent gene regulation in the liver. We report here a peculiar phenotype of Usf2(-/-) mice that progressively develop multivisceral iron overload; plasma iron overcomes transferrin binding capacity, and nontransferrin-bound iron accumulates in various tissues including pancreas and heart. In contrast, the splenic iron content is strikingly lower in knockout animals than in controls. To identify genes that may account for the abnormalities of iron homeostasis in Usf2(-/-) mice, we used suppressive subtractive hybridization between livers from Usf2(-/-) and wild-type mice. We isolated a cDNA encoding a peptide, hepcidin (also referred to as LEAP-1, for liver-expressed antimicrobial peptide), that was very recently purified from human blood ultrafiltrate and from urine as a disulfide-bonded peptide exhibiting antimicrobial activity. Accumulation of iron in the liver has been recently reported to up-regulate hepcidin expression, whereas our data clearly show that a complete defect in hepcidin expression is responsible for progressive tissue iron overload. The striking similarity of the alterations in iron metabolism between HFE knockout mice, a murine model of hereditary hemochromatosis, and the Usf2(-/-) hepcidin-deficient mice suggests that hepcidin may function in the same regulatory pathway as HFE. We propose that hepcidin acts as a signaling molecule that is required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages.
We recently reported the hemochromatosis-like phenotype observed in our Usf2 knockout mice. In these mice, as in murine models of hemochromatosis and patients with hereditary hemochromatosis, iron accumulates in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system is spared from this iron loading. We suggested that this phenotypic trait could be attributed to the absence, in the Usf2 knockout mice, of a secreted liver-specific peptide, hepcidin. We conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. This question was addressed by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin promoter. We found that the majority of the transgenic mice were born with a pale skin and died within a few hours after birth. These transgenic animals had decreased body iron levels and presented severe microcytic hypochromic anemia. So far, three mosaic transgenic animals have survived. They were unequivocally identified by physical features, including reduced body size, pallor, hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikylocytosis and hypochromia, which are features characteristic of iron-deficiency anemia. These results strongly support the proposed role of hepcidin as a putative iron-regulatory hormone. The animal models devoid of hepcidin (the Usf2 knockout mice) or overexpressing the peptide (the transgenic mice presented in this paper) represent valuable tools for investigating iron homeostasis in vivo and for deciphering the molecular mechanisms of hepcidin action.
Accumulation of reactive iron in acute and chronic lung disease suggests that iron-driven free radical formation could contribute to tissue injury. Safe transport and sequestration of this metal is likely to be of importance in lung defense. We provide evidence for the expression and iron-induced upregulation of the metal transporter protein-1 (MTP1) genes in human and rodent lung cells at both the protein and mRNA levels. In human bronchial epithelial cells, a 3.8-fold increase in mRNA level and a 2.4-fold increase in protein level of MTP1 were observed after iron exposure. In freshly isolated human macrophages, as much as an 18-fold increase in the MTP1 protein level was detected after incubation with an iron compound. The elevation in expression of MTP1 gene was also demonstrated in iron-instilled rat lungs and in hypotransferrinemic mouse lungs. This is similar to our previous findings with divalent metal transporter-1 (DMT1), an iron transporter that is required for iron uptake and intracellular iron trafficking. These studies suggest the presence of iron mobilization and/or detoxification pathways in the lung that are crucial for iron homeostasis and lung defense.
Animal models indicate that the antimicrobial peptide hepcidin (HAMP; OMIM 606464) is probably a key regulator of iron absorption in mammals. Here we report the identification of two mutations (93delG and 166C-->T) in HAMP on 19q13 in two families with a new type of juvenile hemochromatosis.
Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.
Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
Ferroportin 1 (FPN1) is transmembrane protein involved in iron homeostasis. In the duodenum, FPN1 localizes to the basolateral surface of enterocytes where it appears to export iron out of the cell and into the portal circulation. FPN1 is also abundantly expressed in reticuloendothelial macrophages of the liver, spleen, and bone marrow, suggesting that this protein serves as an iron exporter in cells that recycle iron from senescent red blood cells. To directly test the hypothesis that FPN1 functions in the export of iron after erythrophagocytosis, FPN1 was stably expressed in J774 mouse macrophages by using retroviral transduction, and release of ⁵⁹Fe after phagocytosis of ⁵⁹Fe-labeled rat erythrocytes was measured. J774 cells overexpressing FPN1 released 70% more ⁵⁹Fe after erythrophagocytosis than control cells, consistent with a role in the recycling of iron from senescent red cells. Treatment of cells with the peptide hormone hepcidin, a systemic regulator of iron metabolism, dramatically decreased FPN1 protein levels and significantly reduced the efflux of ⁵⁹Fe after erythrophagocytosis. Subsequent fractionation of the total released ⁵⁹Fe into heme and nonheme compounds revealed that hepcidin treatment reduced the release of nonheme ⁵⁹Fe by 50% and 25% from control and FPN1-overexpressing cells, respectively, but did not diminish efflux of ⁵⁹Fe-heme. We conclude that FPN1 is directly involved in the export of iron during erythrocyte-iron recycling by macrophages.
• reticuloendothelial cell
• reticuloendothelial system
Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin-ferroportin interaction in iron homeostasis.
Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse. A single intraperitoneal injection of hepcidin caused a rapid fall of serum iron in a dose-dependent manner, with a 50-microg dose resulting in iron levels 80% lower than in control mice. The full effect was seen within only 1 hour, consistent with a blockade of iron export from tissue stores and from macrophages involved in iron recycling. Serum iron remained suppressed for more than 48 hours after injection. Using radiolabeled hepcidin, we demonstrated that the serum concentration of hepcidin at the 50-microg dose was 1.4 microM, consistent with the inhibitory concentration of 50% (IC50) of hepcidin measured in vitro. Radiolabeled hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum. Our study highlights the central role of the hepcidin-ferroportin interaction in iron homeostasis. The rapid and sustained action of a single dose of hepcidin makes it an appealing agent for the prevention of iron accumulation in hereditary hemochromatosis.
The hepatic peptide hormone hepcidin is the central regulator of iron metabolism and mediator of anemia of inflammation. To date, only one specific immuno-dot assay to measure hepcidin in urine had been documented. Here we report an alternative approach for quantification of hepcidin in urine by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Peptide peaks were detected corresponding to the 3 forms of hepcidin normally found in urine. The identity of the peptide peak equivalent to hepcidin-25 was confirmed using synthetic human hepcidin-25. Validation of our MS data on samples with various hepcidin levels showed a strong correlation with previous immuno-dot assay results (Spearman R = 0.9275, P < .001). Most importantly, this hepcidin assay clearly discriminates between relevant clinical iron disorders. In conclusion, this novel MS urine hepcidin assay is easy to perform and available to a wide audience. This enables the implementation of hepcidin measurements in large clinical studies.
Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the "iron hormone" hepcidin which then controls intestinal iron absorption.
Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads
to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin
is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here
we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded,
leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete
a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the
cell surface.
Iron has the capacity to accept and donate electrons readily, interconverting between ferric (Fe2+) and ferrous (Fe3+) forms. This capability makes it a useful component of cytochromes, oxygen-binding molecules (i.e., hemoglobin and myoglobin), and many enzymes. However, iron can also damage tissues by catalyzing the conversion of hydrogen peroxide to free-radical ions that attack cellular membranes, proteins, and DNA. Proteins sequester iron to reduce this threat. Iron ions circulate bound to plasma transferrin and accumulate within cells in the form of ferritin. Iron protoporphyrin (heme) and iron–sulfur clusters serve as enzyme cofactors. Under normal circumstances, only trace amounts . . .
We have reported that serum IL-6 level was related with the degree of anemia in monkey collagen-induced arthritis (CIA). In this study, we examined whether IL-6 blockade ameliorated an anemia in monkey CIA. CIA was induced by twice immunization of bovine type II collagen with adjuvant. When anemia became evident, anti-IL-6 receptor antibody, tocilizumab was intravenously injected once a week for 4 weeks. Controls received PBS in a same manner. Hematological and biochemical parameters were measured regularly and serum hepcidin-25 levels were measured by SELDI-TOF mass spectrometry. Moreover, hepcidin mRNA induction in Hep3B cells by serum from arthritic monkeys was examined by real-time PCR. Administration of tocilizumab rapidly decreased CRP levels and improved iron-deficient anemia within 1 week. Tocilizumab induced rapid but transient reduction in serum hepcidin-25. Hepcidin mRNA expression was more potently induced by serum from arthritic monkey and this was inhibited by the addition of tocilizumab. Blockade of IL-6 signaling rapidly improved anemia in monkey arthritis via the inhibition of IL-6-induced hepcidin production.
The circulating hormone hepcidin plays a central role in iron homeostasis. Our goal was to establish an ex vivo iron-sensing model and to characterize the molecular mechanisms linking iron to hepcidin.
Murine hepatocytes were isolated by the collagenase method, either from wild type or HFE knockout mice, and cultured 42 h without serum before treatments.
After 42 h of serum-free culture, hepcidin gene expression was undetectable in the hepatocytes. Hepcidin gene expression could, however, be re-activated by an additional 24 h of incubation with 10% serum. Interestingly, addition of 30 microM holotransferrin consistently increased serum-dependent hepcidin levels 3- to 5-fold. The effects of serum and serum+holotransferrin were direct, transcriptional, independent of de novo protein synthesis and required the presence of bone morphogenetic protein. Transferrin receptor-2 activation by its ligand holotransferrin led to extracellular signal regulated kinase (ERK)/mitogen activated protein kinase pathway stimulation and the ERK specific inhibitor U0-126 blunted holotransferrin-mediated induction of hepcidin. ERK activation by holotransferrin provoked increased levels of phospho-Smad1/5/8 highlighting cross-talk between the bone morphogenetic protein/hemojuvelin and ERK1/2 pathways. Finally, we demonstrated, using hepatocytes isolated from Hfe(-/-) mice, that HFE was not critical for the hepcidin response to holotransferrin but important for basal hepcidin expression.
We demonstrate that hepatocytes are liver iron-sensor cells and that transferrin receptor-2, by signaling through the ERK1/2 pathway, and bone morphogenetic protein/hemojuvelin, by signaling through the Smad pathways, coordinately regulate the iron-sensing machinery linking holotransferrin to hepcidin.
Hepcidin is known to be a key systemic iron-regulatory hormone which has been demonstrated to be associated with a number of iron disorders. Hepcidin concentrations are increased in inflammation and suppressed in hemochromatosis. In view of the role of hepcidin in disease, its potential as a diagnostic tool in a clinical setting is evident. This study describes the development of a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay for the quantitative determination of hepcidin concentrations in clinical samples. A stable isotope labeled hepcidin was prepared as an internal standard and a standard quantity was added to urine samples. Extraction was performed with weak cation-exchange magnetic nanoparticles. The basic peptides were eluted from the magnetic nanoparticles using a matrix solution directly onto a target plate and analyzed by MALDI-TOF MS to determine the concentration of hepcidin. The assay was validated in charcoal stripped urine, and good recovery (70-80%) was obtained, as were limit of quantitation data (5 nmol/L), accuracy (RE <10%), precision (CV <21%), within -day repeatability (CV <13%) and between-day repeatability (CV <21%). Urine hepcidin levels were 10 nmol/mmol creatinine in healthy controls, with reduced levels in hereditary hemochromatosis (P < 0.000005) and elevated levels in inflammation (P < 0.0007). In summary a validated method has been developed for the determination of hepcidin concentrations in clinical samples.
Hepcidin, a 25-amino acid peptide hormone, plays a crucial regulatory role in iron metabolism. Elevated hepcidin has been observed in response to inflammation and is speculated to be a causative factor in inflammatory anemia due to induction of functional iron deficiency. Hepcidin has been suggested as a biomarker of anemia of inflammation. An accurate assessment of human serum hepcidin is critical to understand its role in anemia.
An LC-MS/MS method was developed to quantify hepcidin in human serum using chemically synthesized hepcidin as a standard and stable isotope labeled hepcidin as internal standard. Rabbit serum was used as a surrogate matrix for standards due to the presence of endogenous hepcidin in human serum. The method was validated to FDA criteria for bioanalytical assays.
The calibration curve was validated over the range of 2.5 to 500 ng/mL. Hepcidin was stable in serum for at least 16 h at room temperature, 90 days at -60 to -80 degrees C, and after three F/T cycles. Interday accuracy (% RE) and precision (%CV) were -11.2% and 5.6%, respectively at the LLOQ, and less than +/-7.0% and 9.2%, respectively for higher concentrations. The mean accuracy of quality control samples (5.00, 15.0, 100 and 400 ng/mL) in 21 analytical batches was between -0.7 and +2.1%, with mean precision between 5.1% and 13.4%. Hepcidin was below 2.5 ng/mL in 31 of 60 healthy subjects, while the mean concentration was less than 10 ng/mL. Sepsis and chronic kidney disease patients had mean serum concentrations of 252 ng/mL (n=16, median 121 ng/mL) and 99 ng/mL (n=50, median 68 ng/mL), respectively.
A fully validated LC-MS/MS method has been described for the determination of hepcidin in human serum. This method was applied to the determination of hepcidin in over 1200 human samples.
The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein HFE. They have lower levels of hepcidin than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the alpha3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE alpha3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf.
In patients with chronic kidney disease, erythropoietin resistance is common, costly, and has implications beyond the management of anemia because the presence of erythropoietin resistance portends mortal outcomes. Exploring the provenance of erythropoietin resistance may be facilitated by the consideration of the pathogenetic triad of iron-restricted erythropoiesis, inflammation, and bone marrow suppression. Challenging to diagnose because of difficulty in interpreting tests of iron deficiency, iron-restricted erythropoiesis should be considered in patients who require high doses of erythropoietin, have low transferrin saturation (eg, <20%-25%), and do not have very high ferritin (eg, <1,200 ng/mL); a therapeutic trial of intravenous iron may be worthwhile. Aluminum intoxication is a rare cause of iron-restricted erythropoiesis that may manifest as microcytic hypochromic anemia. A decrease in serum albumin concentration may signal the presence of inflammation, which may be manifest (such as because of a recent illness or infection) or occult; the latter include clotted synthetic angioaccess, failed renal allograft, dialysis catheter, periodontal disease, underlying malignancy, or uremia per se. Marrow hyporesponsiveness may be improved by increasing the delivered dialysis dose, using ultrapure dialysate, maintaining adequate vitamin B12 and folate stores, or by treating hyperparathyroidism. In summary, improving the outcomes of erythropoietin-resistant patients will require complete patient assessment that goes beyond considerations of iron and erythropoietin dose alone. Given that erythropoietin dose is associated with mortality, mitigating erythropoietin resistance has the potential to improve patient outcomes.
The liver peptide hepcidin regulates body iron, is upregulated in iron overload and inflammation, and is downregulated in iron deficiency/hypoxia. The transmembrane serine protease matriptase-2 (TMPRSS6) inhibits the hepcidin response and its mutational inactivation causes iron-deficient anemia in mice and humans. Here we confirm the inhibitory effect of matriptase-2 on hepcidin promoter; we show that matriptase-2 lacking the serine protease domain, identified in the anemic Mask mouse (matriptase-2(MASK)), is fully inactive and that mutant R774C found in patients with genetic iron deficiency has decreased inhibitory activity. Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma membrane; matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity. Matriptase-2 interacts with HJV through the ectodomain since the interaction is conserved in matriptase-2(MASK). The expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and its interaction with HJV.
Clinicians frequently identify anemia in their older patients, but national data on the prevalence and causes of anemia in this population in the United States have been unavailable. Data presented here are from the noninstitutionalized US population assessed in the third National Health and Nutrition Examination Survey (1988-1994). Anemia was defined by World Health Organization criteria; causes of anemia included iron, folate, and B(12) deficiencies, renal insufficiency, anemia of chronic inflammation (ACI), formerly termed anemia of chronic disease, and unexplained anemia (UA). ACI by definition required normal iron stores with low circulating iron (less than 60 microg/dL). After age 50 years, anemia prevalence rates rose rapidly, to a rate greater than 20% at age 85 and older. Overall, 11.0% of men and 10.2% of women 65 years and older were anemic. Of older persons with anemia, evidence of nutrient deficiency was present in one third, ACI or chronic renal disease or both was present in one third, and UA was present in one third. Most occurrences of anemia were mild; 2.8% of women and 1.6% of men had hemoglobin levels lower than 110 g/L (11 g/dL). Therefore, anemia is common, albeit not severe, in the older population, and a substantial proportion of anemia is of indeterminate cause. The impact of anemia on quality of life, recovery from illness, and functional abilities must be further investigated in older persons.
Hereditary hemochromatosis is a common disorder of iron metabolism most frequently associated with mutations in the HFE gene. Hereditary hemochromatosis may be caused by other less common genetic mutations including those in the ferroportin gene. Whereas hereditary hemochromatosis associated with HFE mutations is an autosomal recessive disorder, essentially all cases of hereditary hemochromatosis associated with ferroportin mutations follow an autosomal dominant pattern of inheritance, and most cases are notable for the lack of an elevated transferrin saturation and presence of iron deposition in Kupffer cells. This report describes the clinical and laboratory features of a family with hereditary hemochromatosis associated with a previously unrecognized ferroportin mutation (Cys326Ser). Three generations of the family are described. The disease in this family is notable for young age at onset, elevated transferrin saturation values, and hepatocyte iron deposition. The distinct molecular and clinical features reflect the heterogeneous nature of this disease.
Ferroportin 1 (FPN1; aka MTP1, IREG1, and SLC40A1), which was originally identified as a basolateral iron transporter crucial for nutritional iron absorption in the intestine, is expressed in airway epithelia and upregulated when these cells are exposed to iron. Using immunofluorescence labeling and confocal microscopic imaging techniques, we demonstrate that in human and rodent lungs, FPN1 localizes subcellularly to the apical but not basolateral membrane of the airway epithelial cells. The role of airway epithelial cells in iron mobilization in the lung was studied in an in vitro model of the polarized airway epithelium. Normal human bronchial epithelial cells, grown on membrane supports until differentiated, were exposed to iron, and the efficiency and direction of iron transportation were studied. We found that these cells can efficiently take up iron across the apical but not basolateral surface in a concentration-dependent manner. Most of the iron taken up by the cells is then released into the medium within 8 h in the form of less reactive protein-bound complexes including ferritin and transferrin. Interestingly, iron release also occurred across the apical but not basolateral membrane. Our findings indicate that FPN1, depending on its subcellular location, could have distinct functions in iron homeostasis in different cells and tissues. Although it is responsible for exporting nutrient iron from enterocytes to the circulation in the intestine, it could play a role in iron detoxification in airway epithelial cells in the lung.
Acute and chronic inflammatory states are associated with many changes in intracellular iron metabolism including sequestration of iron in the mononuclear-phagocyte system (MPS) and a decline in serum iron. Previous work in rodent models of acute inflammation has demonstrated inflammation-induced downregulation of intestinal and MPS iron exporter, ferroportin 1, mRNA and protein. In addition, these models have also demonstrated hepatic induction of mRNA of the small 25 amino acid peptide hepcidin. Hepcidin has been hypothesized to be the mediator of iron- and inflammation-induced changes in iron metabolism. The molecular details of the connection between iron metabolism, hepcidin and inflammation have become clearer with the recent finding of hepcidin-induced internalization and degradation of FPN1. The work presented here demonstrates that the lipopolysaccharide-induced splenic macrophage FPN1 mRNA downregulation is not dependent upon the action of a single cytokine such as IL-6, IL-1 or TNF-alpha because mice deficient in these pathways downregulate FPN1 normally. Furthermore, hepcidin is also synthesized in the spleen of normal mice and induced by lipopolysaccharide. Additionally, in vitro, splenic adherent cells produce hepcidin in response to lipopolysaccharide in an IL-6-dependent manner. There appear to be both probable transcriptional and post-transcriptional control of FPN1 expression by lipopolysaccharide-induced inflammation. The former effect is on mRNA expression and is independent of hepcidin, whereas the latter is IL-6- and hepcidin-dependent.
Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphatidylinositol anchor, suggesting that it can be present in either a soluble or a cell-associated form. Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. However, neither the specific role of hemojuvelin in maintaining iron homeostasis nor its relationship to hepcidin has been experimentally established. In this study we used hemojuvelin-specific siRNAs to vary hemojuvelin mRNA concentration and showed that cellular hemojuvelin positively regulated hepcidin mRNA expression, independently of the interleukin 6 pathway. We also showed that recombinant soluble hemojuvelin (rs-hemojuvelin) suppressed hepcidin mRNA expression in primary human hepatocytes in a log-linear dose-dependent manner, suggesting binding competition between soluble and cell-associated hemojuvelin. Soluble hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro. In cells engineered to express hemojuvelin, soluble hemojuvelin release was progressively inhibited by increasing iron concentrations. We propose that soluble and cell-associated hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration.
Ferroportin (SLC40A1) is an iron transporter postulated to play roles in intestinal iron absorption and cellular iron release. Hepcidin, a regulatory peptide, binds to ferroportin and causes it to be internalized and degraded. If ferroportin is the major cellular iron exporter, ineffective hepcidin function could explain manifestations of human hemochromatosis disorders. To investigate this, we inactivated the murine ferroportin (Fpn) gene globally and selectively. Embryonic lethality of Fpn(null/null) animals indicated that ferroportin is essential early in development. Rescue of embryonic lethality through selective inactivation of ferroportin in the embryo proper suggested that ferroportin has an important function in the extraembryonic visceral endoderm. Ferroportin-deficient animals accumulated iron in enterocytes, macrophages, and hepatocytes, consistent with a key role for ferroportin in those cell types. Intestine-specific inactivation of ferroportin confirmed that it is critical for intestinal iron absorption. These observations define the major sites of ferroportin activity and give insight into hemochromatosis.
A new inherited disorder of iron metabolism, hereafter called “the ferroportin disease,” is increasingly recognized worldwide. The disorder is due to pathogenic mutations in the SLC40A1 gene encoding for a main iron export protein in mammals, ferroportin1/IREG1/MTP1, and it was originally identified as an autosomal-dominant form of iron overload not linked to the hemochromatosis (HFE) gene. It has distinctive clinical features such as early increase in serum ferritin in spite of low-normal transferrin saturation, progressive iron accumulation in organs, predominantly in reticuloendothelial macrophages, marginal anemia with low tolerance to phlebotomy. Ferroportin mutations have been reported in many countries regardless of ethnicity. They may lead to a loss of protein function responsible for reduced iron export from cells, particularly reticuloendothelial cells. Now, the disorder appears to be the most common cause of hereditary iron overload beyond HFE hemochromatosis.
Hepcidin, a regulator for iron homeostasis, is induced by inflammation and iron burden and suppressed by anemia and hypoxia. This study was conducted to determine the hepcidin levels in patients with congenital chronic anemias.
Forty-nine subjects with anemia, varying degrees of erythropoiesis and iron burden were recruited. Eight children with immune thrombocytopenia were included as approximate age-matched controls. Routine hematologic labs and urinary hepcidin (uhepcidin) levels were assessed. For thalassemia major (TM) patients, uhepcidin was obtained pre- and post-transfusion.
In TM, uhepcidin levels increased significantly after transfusion, demonstrated wide variance, and the median did not significantly differ from controls or thalassemia intermedia (TI). In both thalassemia syndromes, the hepcidin to ferritin ratio, a marker of the appropriateness of hepcidin expression relative to the degree of iron burden, was low compared to controls. In TI and sickle cell anemia (SCA), median uhepcidin was low compared to controls, P = 0.013 and <0.001, respectively. In thalassemia subjects, uhepcidin levels were positively associated with ferritin. In subjects with SCA, uhepcidin demonstrated a negative correlation with reticulocyte count.
This study examines hepcidin levels in congenital anemias. In SCA, hepcidin was suppressed and inversely associated with erythropoietic drive. In thalassemic syndromes, hepcidin was suppressed relative to the degree of iron burden. Transfusion led to increased uhepcidin. In thalassemia, the relative influence of known hepcidin modifiers was more difficult to assess. In thalassemic syndromes where iron overload and anemia have opposing effects, the increased erythropoietic drive may positively influence hepcidin production.
Hepcidin, the principal iron regulatory hormone, regulates the absorption of iron from the diet and the mobilization of iron from stores. Previous studies indicated that hepcidin is suppressed during anemia, a response that would appropriately increase the absorption of iron and its release from stores. Indeed, in the mouse model, hepcidin-1 was suppressed after phlebotomy or erythropoietin administration but the suppression was reversed by inhibitors of erythropoiesis. The suppression of hepcidin necessary to match iron supply to erythropoietic demand thus requires increased erythropoiesis and is not directly mediated by anemia, tissue hypoxia, or erythropoietin.
The advent of the genetics era has profoundly changed the way we look at iron related diseases, particularly hemochromatosis. New discoveries have challenged historical concepts about the disease, such as its monogenic nature, intestinal origin or complete phenotypic penetrance. This review presents a new concept of hemochromatosis which stems from the idea that, beyond their genetic diversities, all known hemochromatoses have in common the same metabolic abnormality: the genetically determined failure to prevent unneeded iron from entering the circulatory pool. Inappropriate levels of hepcidin, the iron hormone, appear now as the central pathogenic event in all forms of hemochromatosis: depending on the protein involved, and its effect on hepatic production of hepcidin, the phenotype varies, ranging from massive early-onset iron loading with severe organ disease (e.g., associated with homozygous mutations of hemojuvelin or hepcidin itself) to the milder late-onset phenotype characterizing the classic and highly prevalent HFE-related form or the rare transferrin receptor 2-related form. In vitro and in vivo studies will be needed to dissect the consequences of each hereditary hemochromatosis allele and increase our understanding of the precise contribution of each gene to the hereditary hemochromatosis phenotype.
Hepcidin is an acute-phase response peptide. We have investigated the possible involvement of hepcidin in massive obesity, a state of chronic low-grade inflammation. Three groups of severely obese patients with or without diabetes or nonalcoholic steatohepatitis were investigated.
Hepcidin expression was studied in liver and adipose tissue of these patients. Hepcidin regulation was investigated in vitro by adipose tissue explant stimulation studies.
Hepcidin was expressed not only in the liver but also at the messenger RNA (mRNA) and the protein levels in adipose tissue. Moreover, mRNA expression was increased in adipose tissue of obese patients. The presence of diabetes or NASH did not modify the hepcidin expression levels in liver and adipose tissue. In adipose tissue, mRNA expression correlated with indexes of inflammation, interleukin-6, and C-reactive protein. Interleukin-6 also promoted in vitro hepcidin expression. A low transferrin saturation ratio was observed in 68% of the obese patients; moreover, 24% of these patients presented with anemia. The observed changes in iron status could be due to the role of hepcidin as a negative regulator of intestinal iron absorption and macrophage iron efflux. Interestingly, a feedback control mechanism on hepcidin expression related to low transferrin saturation occurred in the liver but not in the adipose tissue.
Hepcidin is a proinflammatory adipokine and may play an important role in hypoferremia of inflammation in obese condition.