Regulation Of Iron Absorption Research Articles

The Effect of Vitamin D3 on Hepcidin and IL-8 Expression in Monocytes

Background: It has been shown that optimal levels of vitamin D3 offer many health benefits and confer resistance to many diseases, notably those related to metabolic syndrome. Vitamin D3 status is of particular relevance in elderly populations wherein deficiency of this vitamin is increasingly being reported. Anaemia is also a common finding with approximately 10 percent of persons older than 65 years of age suffering from mild to moderate anaemia. In about 1/3 of these patients, the type of anaemia observed is anaemia of inflammation (AI) and is linked to the presence of high levels of the iron regulatory peptide hormone hepcidin. Hepcidin is antimicrobial peptide (AMP) structurally similar to other members of this family, in particular the defensins. Hepcidin negatively regulates iron absorption in the intestine and inhibits reticuloendothelial macrophages from releasing recycled iron. During periods of infection and inflammation, hepcidin levels increase due to the action of many cytokines including IL-8. Hepcidin has therefore a dual role in the immune response. It has been demonstrated that in monocytes, vitamin D3 is also able to induce the expression of the AMP cathelicidin due to the presence of a vitamin D3 response element (VDRE) in promoter regions of the cathelicidin ( Camp ) gene. It is however currently unknown whether vitamin D3 also plays a role in the signalling pathway that controls hepcidin expression. Methods: In the present work, we address the possibility that vitamin D3 is able to modulate hepcidin expression by stimulating monocytic THP-1 cells with varying concentrations of vitamin D3, extracting mRNA and ascertaining hepcidin expression by RT-PCR and gel electrophoresis. We also postulate that vitamin D3 stimulation in these cells is able to regulate the expression of IL-8 and use the supernatant from cell culture to explore this hypothesis. Results: The results presented here confirm previous reports that these cells constitutively express hepcidin mRNA and extend these observations by demonstrating that vitamin D3 can indeed modulate hepcidin expression. Modulation was dependent on the concentration of vitamin D3 used with maximal effect at 10 nM under the conditions used. Results also demonstrate that non-stimulated THP-1 supernatants release low levels of IL-8 and treatment with vitamin D3 at all concentrations tested reduced the levels of IL-8. A further observation was that IL-8 levels were very similar after 4 and 20 hours of vitamin D3 treatment, suggesting that the production and secretion of IL-8 happened at relatively early time points. Conclusion : The present work has demonstrated that THP-1 cells when stimulated with higher concentrations of vitamin D3 (10 and 100 nM) decrease their expression of hepcidin mRNA while no change in the housekeeping gene GAPDH was observed. This downregulation of hepcidin mRNA expression may be translated in vivo with increases in serum iron and therefore may be potentially relevant in the treatment of AI/ACD. The present work also confirms previous reports that stimulation with vitamin D3 causes THP-1 cells to decrease the production of the pro-inflammatory cytokine IL-8, suggesting that vitamin D3 insufficiency may play a role in inflammatory disease and may offer new therapeutic options. doi: http://dx.doi.org/10.4021/jh71e

Low preoperative hepcidin concentration as a risk factor for mortality after cardiac surgery: A pilot study

Hepcidin regulates iron absorption and recycling and is central to host defense, protection from reactive iron species, and a biomarker of iron-related pathophysiology. We assessed the value of hepcidin measured preoperatively for the prediction of in-hospital mortality and renal outcomes. We studied 100 adult patients undergoing cardiac surgery in the control arm of a randomized, controlled trial. Plasma and urine were sampled before induction of anesthesia, and hepcidin-25 was quantified by competitive enzyme-linked immunoassay. Renal outcomes were acute kidney injury defined by risk, injury, failure, loss of function, end-stage renal disease (RIFLE) classification and need for renal replacement therapy. Variables with the potential to influence hepcidin expression were investigated. Low preoperative hepcidin concentration in urine (median, 15.3 ng/mL; 25-75 percentiles, 0-129.1) and plasma (median, 49.2 ng/mL; 25th-75th percentile, 0-52.2) predicted mortality (area under the curve-receiver operating characteristic [AUC-ROC] for urine hepcidin, 0.89; 95% confidence interval, 0.73-0.99; cutoff, 130 ng/mL; sensitivity, 73%; specificity, 100%; and AUC-ROC for plasma hepcidin, 0.90; 95% confidence interval, 0.80-0.99; cutoff, 55 ng/mL; sensitivity, 83%; specificity, 100%). Survivors had median preoperative hepcidin concentrations of 325.3 ng/mL (25th-75th percentile, 120-770.1 ng/mL) in urine and 113.1 ng/mL (25th-75th percentile, 77.7-203.1 ng/mL) in plasma. Preoperative serum creatinine did not predict mortality (AUC-ROC, 0.50; 95% confidence interval, 0.10-0.94). Furthermore, preoperative urine, plasma hepcidin, and serum creatinine did not distinguish patients requiring postoperative renal replacement therapy from those without (urine: AUC-ROC, 0.62; 95% confidence interval, 0.38-0.86; plasma: AUC-ROC, 0.63; 95% confidence interval, 0.34-0.91; serum creatinine: AUC-ROC, 0.61; 95% confidence interval, 0.22-0.99). Preoperative renal function and hemoglobin did not correlate with hepcidin indices whereas plasma markers of inflammation did. Low preoperative hepcidin concentration might be a risk factor for in-hospital mortality. Findings should be validated in larger patient cohorts with a greater number of events.

Interaction between iron/folic acid and malaria

This abstract is submitted as part of the round-table discussion sponsored by Sight and Life. A recent trial reinforced earlier concerns that iron supplementation can increase malaria rates. The World Health Organization subsequently restricted its recommendations in malaria-endemic areas from universal supplementation to targeted supplementation of iron-deficient children, but continues to advocate universal supplementation in pregnancy. Resurgent interest in iron has led to further studies to assess its safety, particularly in pregnant women; to identify markers for rapid, low-cost screening for deficiency; and to develop safe but efficacious iron interventions. The hepcidin-axis recently emerged as a newly discovered arm of the innate immune system. Hepcidin is now known to regulate iron absorption and metabolism, but also to mediate impaired recycling and absorption of iron in infections. Current evidence suggests that plasma hepcidin concentration may predict haematological and infectious responses to iron, at least in the short term, and that deliberately altering hepcidin concentrations may result in new strategies to control infections by Plasmodium and other iron-requiring pathogens. Folic acid supplementation continues to be recommended around conception and during pregnancy, and international agencies have recommended additional measures to increase the intake of folic acid. Plasmodium parasites can utilise exogenous folate, however, and several trials suggest that folic acid supplementation can reduce the efficacy of antifolate drugs used for malaria control. A better understanding is required of the controversies of interventions to increase folate status and the safety of interventions to improve folate status in malaria-endemic countries.

Role of Quercetin on iron homeostasis

Iron is crucial in processes such as oxygen binding in haemoglobin, electron transport in mitochondria, cell proliferation and differentiation, etc. Insufficient iron regulation can lead to either accumulation of iron that enhances oxidative stress or iron deficiency leading to altered cell growth and metabolism. As there is no regulated physiological mechanism for excretion of iron, iron homeostasis is maintained primarily by regulating iron absorption. Dietary iron content and other dietary constituents can have a major impact on iron homeostasis. Flavonoids are a group of compounds found in the diet either naturally or added as food additives. Therefore interaction of these compounds with iron is of interest. Quercetin, one of the most abundant flavonols in the diet, is an effective iron chelator and also acts as an antioxidant by modulating expression of antioxidant enzymes. Both of these properties of quercetin therefore can have an effect on iron absorption. The aim of this work was to elucidate the effect of quercetin administered by gavage or intraperitionally (IP) on iron uptake. Sprague Dawley male rats, fed on an iron deficient or iron replete diet for two weeks, were used as the animal model. Gene expression of selected intestinal proteins (DMT1, FPN, Dcytb, GLUT1 and SGLT1) was quantitated by Real-time PCR. Intestinal iron absorption was measured in another group of animals using the in situ loop method and radioactive iron. Additionally, levels of iron and transferrin saturation in serum, and nonheme iron in duodenum, liver and spleen, were determined. Results were obtained during 13 different treatments on animal models. Study showed that quercetin affects iron homeostasis by changing expression of proteins involved in iron absorption in greater amount when administrated orally than IP. Furthermore, after longer oral treatment with quercetin, animals became iron deficient as both liver and spleen iron levels decreased significantly, 1.2 and 1.1 fold, respectively. These results confirmed negative effects of polyphenols on iron adsorption when consumed in a diet for a longer time. Additionally, when administrated orally, quercetin significantly upregulated SGLT1 transporter, namely 1.8 and 1.6 fold, 18 hours and 5 hours before being sacrificed. These results indicate that quercetin is probably transported by SGLT1 in the duodenum. Moreover, in uptake experiments where quercetin was introduced into the duodenum together with radioactive iron, there was a significant difference in levels of radioactive iron accumulated by duodenal mucosa (increase 2.7 fold) or transferred to serum (decrease 7.3 fold), compared to controls. The most probable explanation is that quercetin chelates iron, and that the complex is transported into enterocytes, but is not further transported into circulation. However, other uptake experiments showed no change in concentration of absorbed iron. Bearing in mind our results and the fact that there was no change in concentration of absorbed iron in the mucosa and circulation during uptake studies, further experiments are needed in order to get a more complete picture of how quercetin affects iron absorption.

Intestinal iron absorption

Intestinal iron absorption is a critical process for maintaining body iron levels within the optimal physiological range. Iron in the diet is found in a wide variety of forms, but the absorption of non-heme iron is best understood. Most of this iron is moved across the enterocyte brush border membrane by the iron transporter divalent metal-ion transporter 1, a process enhanced by the prior reduction of the iron by duodenal cytochrome B and possibly other reductases. Enterocyte iron is exported to the blood via ferroportin 1 on the basolateral membrane. This transporter acts in partnership with the ferroxidase hephaestin that oxidizes exported ferrous iron to facilitate its binding to plasma transferrin. Iron absorption is controlled by a complex network of systemic and local influences. The liver-derived peptide hepcidin binds to ferroportin, leading to its internalization and a reduction in absorption. Hepcidin expression in turn responds to body iron demands and the BMP-SMAD signaling pathway plays a key role in this process. The levels of iron and oxygen in the enterocyte also exert important influences on iron absorption. Disturbances in the regulation of iron absorption are responsible for both iron loading and iron deficiency disorders in humans.

17β-Estradiol Inhibits Iron Hormone Hepcidin Through an Estrogen Responsive Element Half-Site

Interaction of estrogen with iron at the systemic level is long suspected, but direct evidence linking the two is limited. In the present study, we examined the effects of 17β-estradiol (E2) on hepcidin, a key negative regulator of iron absorption from the liver. We found that transcription of hepcidin was suppressed by E2 treatment in human liver HuH7 and HepG2 cells, and this down-regulation was blocked by E2 antagonist ICI 182780. Chromatin immunoprecipitation, deletion, and EMSA detected a functional estrogen responsive element half-site that is located between -2474 and -2462 upstream from the start of transcription of the hepcidin gene. After cloning the human hepcidin promoter into the pGL3Luc-Reporter vector, luciferase activity was also down-regulated by E2 treatment in HepG2 cells. E2 reduced hepcidin mRNA in wild-type mice as well as in hemochromatosis Fe gene knockout mice. In summary, our data suggest that hepcidin inhibition by E2 is to increase iron uptake, a mechanism to compensate iron loss during menstruation. This mechanism may also contribute to increased iron stores in oral contraceptive users.

Abstract 3253: Bone morphogenetic proteins increase hepcidin in breast cancer cells

Abstract Hepcidin is a systemic peptide hormone produced in the liver that regulates iron absorption and recirculation. Induction of hepcidin by inflammatory cytokines has been suggested to contribute to the anemia of inflammation and cancer. Our previous work has shown that synthesis of hepcidin is not confined to the liver, but is also observed in other tissues. In particular, we found that hepcidin is produced in mammary epithelial cells. Further, hepcidin levels increase in a subset of breast cancers, and increased synthesis of hepcidin is associated with poor prognoses in some breast cancer patients (Pinnix et al., 2010). In this work we sought to understand mechanisms regulating hepcidin synthesis in breast cancer, as well as the consequences of hepcidin upregulation. We demonstrate that treatment with bone morphogenetic proteins (BMPs) 2, 4, 6, or 7 results in hepcidin upregulation and concomitant Smad phosphorylation in breast cancer cells. The BMP7-induced hepcidin increase can be diminished by co-treatment of breast cancer cells with the BMP inhibitors, Wise or Noggin. We next assessed the consequence of hepcidin induction. Systemic hepcidin regulates iron by affecting the levels of the iron export protein, ferroportin. Extracellular hepcidin binds to ferroportin on the cell surface, initiating the internalization and degradation of ferroportin. This, in turn, decreases the ferroportin available to facilitate iron export, preventing iron efflux from the cell and increasing cellular iron retention. To test the functionality of this regulatory pathway in breast cancer, we used a hepcidin-specific antibody to deplete cultured breast cancer cells of extracellular hepcidin. We found that antibody-induced hepcidin depletion increased ferroportin protein levels, suggesting that hepcidin-mediated ferroportin regulation occurs in breast cancer cells. Consistent with this finding, we observed that breast cancer cells have increased hepcidin and decreased ferroportin relative to normal mammary epithelial cells. In all, these results raise the possibility that BMP signaling may control hepcidin expression in breast cells, decreasing ferroportin and increasing intracellular iron. The potential for hepcidin to alter iron availability to breast cancer cells on a paracrine level is a novel function for this key systemic iron regulator. Reference Z. K. Pinnix, L. D. Miller, W. Wang, R. D'Agostino Jr., T. Kute, M. C. Willingham, H. Hatcher, L. Tesfay, G. Sui, X. Di, S. V. Torti, F. M. Torti, Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis. Sci. Transl. Med. 2, 43ra56 (2010). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3253. doi:1538-7445.AM2012-3253

The H63D Mutation of the Hemochromatosis Gene is Associated with Sustained Virological Response in Chronic Hepatitis C Patients Treated with Interferon-Based Therapy: A Meta-Analysis

The hemochromatosis (HFE) gene encodes the HFE protein that regulates iron absorption. HFE mutations lead to the hemochromatosis disease of excessive iron absorption. HFE mutations may also influence the sustained virologic response (SVR, long-term virus suppression) in chronic hepatitis C patients treated with interferon-based antiviral therapy. We performed a meta-analysis of all English and Chinese language studies of HFE mutations and SVR in interferon-treated chronic hepatitis C patients indexed in the Medline, PubMed, Embase, and China National Knowledge Infrastructure databases to November 2011. Seven studies involving 605 patients with HFE mutations (homozygous or heterozygous mutation of C282Y, H63D or S65C) and 1279 with wild-type HFE (no mutation of C282Y, H63D or S65C for both alleles) were analyzed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the fixed- or random-effect models. HFE mutations were associated with significantly higher SVR rate (vs. wild-type: OR = 1.56, 95% CI: 1.23-1.97, P < 0.001), indicating that mutation carriers were likely to achieve SVR in response to interferon-based antiviral therapy. Stratification analysis by HFE mutation type revealed that the H63D mutation was associated with a significantly higher SVR rate (OR = 1.60, 95% CI: 1.09-2.34, P = 0.020), while the C282Y mutation was not (OR = 1.19, 95% CI: 0.71-1.98, P = 0.510). Our meta-analysis results indicate that the H63D mutation in HFE is associated with a higher SVR rate in chronic hepatitis C patients treated with interferon-based antiviral therapy.

Hepcidin in Male Double Red Blood Cell Donors - Relationship Between Parameters of Iron Metabolism and Erythropoiesis

Abstract 2109Hemoglobin (Hb) below 12.5g/dL accounts for more than 40% of all blood donor deferrals, and no standardized message is provided to these deferred donors. Furthermore, many donors who meet Hb standards are iron depleted. In light of this, the FDA requested comments on possibly changing the minimal acceptable Hb and/or the inter-donation interval. Here we explore several parameters of iron utilization after red blood cell (RBC) donation to understand its relationship to erythropoiesis.Hepcidin is the central regulator of iron absorption, suppressed by low iron stores. We hypothesize that hepcidin values would identify donors with normal Hb levels and low iron stores and thus identify those who would benefit from iron replacement to prevent future low Hb deferral.We enrolled eligible repeat male double RBC donors randomized to receive placebo (n=5) or iron supplementation (n=5) using 90 mg of elemental iron (feosol caplets). Donors were enrolled on day of donation and were invited to return at 2–4 day intervals during the 14 days following donation to compare with pre-donation markers of erythropoiesis and iron metabolism. In addition, buffy coats were collected on day 0 and again 7–10 days following donation (n=6) to quantify by flow cytometry circulating CD34+ cells as well as numbers of common myeloid progenitors (CMPs) and megakaryocyte erythroid progenitors (MEPs) in study donors.Comparing iron supplemented to placebo receiving volunteers, ferritin was higher at 14 days in iron supplemented donors (18.6±3.9 vs 12.0±1.6 ng/mL) and corresponds with 52% vs. 36% of levels prior to donation relative to placebo (P=0.05). Furthermore, serum hepcidin nadirs earlier and rebounds sooner relative to placebo (15.4±3.2 vs. 6.8±2.1 ng/mL, P=0.05). Serum iron (150±37.1 vs. 60±5.8 mg/dL, P=0.04) and transferrin saturation (39.8±9.8 vs. 16.2±2.1%, P=0.05) are also increased relative to placebo by day 10 following donation. Although we found no difference in recovery of RBC count, hemoglobin, or hematocrit following donation, a trend toward a more sustained elevation in reticulocyte count is present relative to placebo (158±12.1 vs. 118±17.3 × 109 cells/mL, P=0.07). CD34+ cells in circulation are increased following donation in all donors. Furthermore, only donors with baseline ferritin levels >20 ng/mL increased MEPs following donation. These later findings are consistent with expectations of iron regulatory mechanisms influencing erythropoiesis.Taken together, these data suggest that a complex interplay between iron regulatory and erythropoietic mechanisms occurs during recovery from blood donation. Although it is currently unclear how iron regulation affects erythropoiesis, a larger (double) sample size will aid in the generation of criteria for donor iron supplementation. Disclosures:Olbina:Intrinsic LifeSciences LLC: Employment, Equity Ownership; Hepcidin C-ELISA:. Westerman:Intrinsic LifeSciences LLC: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Hepcidin C-ELISA: Patents & Royalties; Centocor-Ortho R&D, Inc.: Honoraria.

Hepcidin: clinical utility as a diagnostic tool and therapeutic target

Iron is essential for life, yet excessive iron can damage tissues and organs. To prevent iron deficiency and overload, iron balance is regulated by the hormone hepcidin. Hepcidin levels increase in response to iron sufficiency, decreasing intestinal iron absorption and inhibiting release of iron from stores and macrophages. Iron deficiency lowers hepcidin, leading to enhanced iron absorption and mobilization of iron from stores. Hepcidin is also increased by inflammation, and has a major role in the anemia of chronic disease. Chronic kidney disease (CKD) is associated with increased hepcidin levels, and this likely contributes to the incidence and severity of anemia, and resistance to erythropoiesis-stimulating agents (ESAs). Elevated hepcidin contributes to the dysregulation of iron homeostasis in CKD. In patients with CKD, although parenteral iron in CKD can bypass some of the iron-blocking effects of hepcidin, free iron and iron stores increase, anemia is only partially corrected, and ESA dose requirements remain significantly higher than physiological replacement. Agents that lower hepcidin or inhibit its actions may be effective strategies to restore normal iron homeostasis, and overcome anemia of chronic kidney disease. We review the regulation of hepcidin, its role in CKD-related anemia, and discuss the potential for hepcidin as a clinical marker, and several investigational methods to lower hepcidin for treatment of anemia in CKD.

Intestinal Hypoxia-inducible Factor-2α (HIF-2α) Is Critical for Efficient Erythropoiesis

Erythropoiesis is a coordinated process by which RBCs are produced. Erythropoietin, a kidney-derived hormone, and iron are critical for the production of oxygen-carrying mature RBCs. To meet the high demands of iron during erythropoiesis, small intestinal iron absorption is increased through an undefined mechanism. In this study, erythropoietic induction of iron absorption was further investigated. Hypoxia-inducible factor-2α (HIF-2α) signaling was activated in the small intestine during erythropoiesis. Genetic disruption of HIF-2α in the intestine abolished the increase in iron absorption genes as assessed by quantitative real-time reverse transcription-PCR and Western blot analyses. Moreover, the increase in serum iron following induction of erythropoiesis was entirely dependent on intestinal HIF-2α expression. Complete blood count analysis demonstrated that disruption of intestinal HIF-2α inhibited efficient erythropoiesis; mice disrupted for HIF-2α demonstrated lower hematocrit, RBCs, and Hb compared with wild-type mice. These data further cement the essential role of HIF-2α in regulating iron absorption and also demonstrate that hypoxia sensing in the intestine, as well as in the kidney, is essential for regulation of erythropoiesis by HIF-2α.

Lack of iron-related phenotype in Sp6 intestinal knockout mice

Based on a microarray study, which demonstrated the upregulation of Sp6 transcriptional factor in iron deficient rat duodenum, we reasoned that SP6 could regulate iron absorption by controlling the expression of iron absorption genes (Collins,2006). For that, we generated Sp6 specific intestinal knockout mice. Our data suggest a lack of transcriptional upregulation of Sp6 in mice in conditions where iron absorption is promoted (phlebotomy, iron deficiency, hpx mouse), and an absence of iron-related phenotype in Sp6 intestinal knockout model. We propose that other Sp6 orthologues may be involved in the genetic response to increase iron absorption, possibly in co-operation with hypoxia inducible factor 2 alpha (HIF-2α)—a newly discovered regulator of iron absorption.

Growth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II

Congenital dyserythropoietic anaemias (CDAs) are heterogeneous, hereditary disorders hallmarked by ineffective erythropoiesis and tissue iron overload. Growth differentiation factor 15 (GDF15) was suggested to mediate iron overload in iron-loading anaemias, such as the thalassaemias and CDAI by suppressing hepcidin, the key regulator of iron absorption. Here, we show that serum GDF15 concentrations are elevated in subjects with CDAI and CDAII. Despite similar disease characteristics, CDAI patients present with significantly higher GDF15 concentrations compared to CDAII patients. Hepcidin concentrations are inappropriately low in CDAII patients considering the severe hepatic iron overload associated with this disorder. GDF15 significantly correlates with the degree of anaemia (Hb), the response of erythropoiesis (reticulocyte index) as well as with iron availability in the serum (transferrin saturation). The observation that GDF15 is elevated in CDAII patients is consistent with the proposal that GDF15 is among the erythroid factors down-regulating hepcidin and contributing to iron overload in conditions of dyserythropoiesis.

Duodenal cytochrome b (Cybrd 1) and HIF-2α expression during acute hypoxic exposure in mice

Recent evidence suggests that the duodenum can regulate iron absorption independently of hepcidin via the transcription factor Hif-2α acting directly on the transcription of the proteins involved in the iron transport. The current study investigates the temporal relationship between Dcytb and Hif-2α during early hypoxic stimulus in the enterocyte in vivo. Duodenal Dcytb and Hif-2α protein expression was analysed by Western blot technique while gene regulation was determined by quantitative PCR. Both Dcytb and Hif-2α protein expression were increased during the first hours of hypoxic duration. A change in hepcidin expression however, was significant only at 72 h hypoxia. Increased iron absorption reported in early hypoxia could be accounted for in part by the enhancement of Dcytb expression by Hif-2α in the duodenum. Modulation of Hif-2α predominates over hepcidin in the regulation of intestinal iron absorption during short hypoxic duration. The intestine exerts regulatory mechanisms in the dietary absorption of iron into systemic circulation.

Hepcidin and Disorders of Iron Metabolism

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.

Molecular mechanism of intestinal iron absorption

Iron is an essential trace metal in the human diet because of its role in a number of metabolic processes including oxygen transport. In the diet, iron is present in two fundamental forms, heme and non-heme iron. This article presents a brief overview of the molecular mechanisms of intestinal iron absorption and its regulation. While many proteins that orchestrate iron transport pathway have been identified, a number of key factors that control the regulation of iron absorption still remain to be elucidated. This review also summarizes new and emerging information about iron metabolic regulators that coordinate regulation of intestinal iron absorption.

Changes of Iron Stores and Duodenal Transepithelial Iron Transfer During Regular Exercise in Rats

It is unclear whether regular exercise depletes body iron stores and how exercise regulates iron absorption. In this study, growing female Sprague-Dawley rats were fed a high-iron diet (300 mg iron/kg) and subjected to swimming for 1, 3, or 12 months. Their body weight, liver nonheme iron content (NHI), spleen NHI, blood hemoglobin (Hb) concentration, hematocrit (Hct), and kinetics of 59Fe transfer across isolated duodenal segments were then compared with sedentary controls. The main results were as follows: exercise for 1 month enhanced the transepithelial 59Fe transfer and increased liver NHI content and Hb concentration; exercise for 3 months inhibited transepithelial 59Fe transfer without affecting the liver and spleen NHI content, Hb concentration, and Hct; exercise for 12 months did not affect these parameters as compared with the corresponding sedentary controls; and the changes in transepithelial iron transfer were not associated with basolateral iron transfer. Our findings demonstrated that chronic, regular exercise in growing rats with a high dietary iron content does not deplete iron stores in the liver and spleen and may possibly enhance or inhibit duodenal iron absorption and even maintain duodenal iron absorption at the sedentary level, at least, in part depending on growth.

A tincture of hepcidin cures all: the potential for hepcidin therapeutics

Iron overload as a result of blood transfusions and excessive intestinal iron absorption can be a complication of chronic anemias such as β-thalassemia. Inappropriately low levels of hepcidin, a negative regulator of iron absorption and recycling, underlie the pathophysiology of the intestinal hyperabsorption. In this issue of the JCI, Gardenghi et al. demonstrate that increasing hepcidin expression to induce iron deficiency in murine β-thalassemia not only mitigates the iron overload, but also the severity of the anemia. These data illustrate the therapeutic potential of modulating hepcidin expression in diseases associated with altered iron metabolism.

Homeostatic Regulation of Iron and Its Role in Normal and Abnormal Iron Status in Infancy and Childhood

Iron is important in neurodevelopment and cognitive function, and globally preventing iron deficiency and iron deficiency anemia remains a high priority. Term breast-fed infants and infants fed an iron-fortified formula usually have a satisfactory iron status during the first 6 months of life, but there are still ambiguities in assessing iron status in infants and how to properly meet their iron requirements. This is particularly evident for preterm infants, who are born with low iron stores, and for whom recommendations for iron provision vary considerably. In part, this may be due to immaturity in the regulation of iron homeostasis in young infants. Whereas 9-month-old infants appear to be able to downregulate iron absorption when being iron replete, 6-month-old infants cannot do this. Iron may be provided as drops or in iron-fortified products, but the forms provided may be metabolized differently, and excess iron in drops may cause adverse effects, possibly due to a limited ability to regulate iron absorption in young infants. Adverse effects are manifested by decreased growth: in well-nourished infants by reduced gain in length, in poorly nourished populations by lower gain in weight. The mechanism behind the decreased growth is not known, but it may involve free radical-mediated effects of iron or an interaction with zinc absorption/homeostasis. It therefore seems that iron drops should not be given to iron-replete infants.

Iron Status in Infants and Relation to Dietary Intake. Part 1: General and Developmental Aspects

Iron deficiency is one of the leading nutritional problems worldwide, affecting an estimated total of about 2 billion individuals. Nearly 40% of children younger than 5 years and about 50% of pregnant women in developing countries are anaemic. However, iron deficiency is also common in women and young children in industrialised countries. Due to developmental and maturational processes and needs, there are some particularities of iron metabolism in infancy and the general regulative mechanisms seem not to be easily applicable in infants. Infants and young children in the period of rapid growth (six to 24 months) are at high risk to develop iron deficiency (ID) or even iron deficiency anaemia (IDA), when their high physiological requirements can not be met by iron absorption from diet. The physiology of iron metabolism during infancy is characterized by developmental changes e.g. in regulation of key intestinal and hepatic proteins regulating iron absorption in response to changing iron status. Considering the long term consequences of ID on the development of motor and cognitive performance, a better understanding of the physiology of iron homeostasis during infancy may help further to improve the control of iron deficiency in infants.