scholarly journals Study on Sucrosomial® Iron Endocytosis-Mediated Uptake and Enterocytes Release

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4892-4892
Author(s):  
Elisa Brilli ◽  
Asperti Michela ◽  
Magdalena Gryzik ◽  
Alessandro Lucchesi ◽  
Giovanni Martinelli ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Phospholipid Bilayer ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Iron Release ◽  
Iron Storage

Abstract Introduction: iron homeostasis is maintained by regulating the iron levels in plasma which is maintained by four coordinated processes: duodenal iron absorption, macrophage iron recycling, hepatic iron storage and erythropoiesis. Iron in the Fe2+ form is transported across the apical duodenal membrane by DMT1 and subsequently transferred to the blood via the iron exporter, Ferroportin the only know cell membrane iron exporter. Due to the presence of two check points at cellular levels, iron absorption and release are mainly regulated, because of this iron containing oral formulations are poorly absorbed and bioavailable. To overcome cellular barriers and increasing the bioavailability of supplemented iron forms, there is a need for new carriers that work protecting the iron as well as enhancing its intestinal absorption and release into the blood stream. Moreover thus reducing dosage and side effects. Sucrosomial® Iron (SI) represents an innovative oral iron-containing carrier in which ferric pyrophosphate is protected by a phospholipid bilayer membrane plus a sucrester matrix. To date, in vitro studies have shown that SI is mostly absorbed as vesicle-like structure, bypassing the conventional iron absorption pathway. Due to its behaviour at the gastrointestinal tract, SI is well tolerated and highly bioavailable compared to conventional iron salts. To deeply understand involvement of endocytosis in SI absorption and release, in vitro experiments using endocytosis and ferroportin inhibitors were carried out Aim: to study Sucrosomial® Iron uptake and release in different in vitro systems. Materials and Methods: CACO-2 and THP1 cells were used to investigate the role of FPN in Sucorsomial Iron release from cells. For release study, CACO-2 cells were exposed for 18h to quercetin (150mmol/L) in order to downregulate FPN expression. CACO-2 quercetin pre-treated cells were co-cultured with TPH1 cells, and SI or FAC were added. However, prior to measure cell Ferritin content, the incubation medium was discarded and cells were washed to remove quercetin. Iron uptake-release analysis was performed using co-culture transwell system between CACO-2 cells and TPH1. To investigate the cellular fate of cellular iron in quercetin treated CACO-2 and TPH1 cells we measured cell ferritin content. To inhibit endocytosis absorption pathway, CACO-2, THP1 and HepG2 cells were pre-treated with PitStop2 and Dyngo 4a inhibitors and then treated with SI, or Ferrous Sulfate (FS) or ferric ammonium citrate (FAC). Cellular Ferritin content was measured. Results: in order to understand the effect of quercetin on iron storage, we used CACO2 and TPH1 cells pre-treated with quercetin and then treated with SI, FAC or nothing (control). Quercetin-SI treated CACO-2 cells showed no differences in Ferritin expression compared to control cells (3,94 ngFTL/mg proteins Vs 4,56 ngFTL/mg proteins) while in quercetin-FAC treated cells ferritin expression was decreased compare to control cells (16,3 ngFTL/mg proteins Vs 27,55 ngFTL/mg proteins). In a similar manner, quercetin-SI treated TPH1 cells didn't show increase in Ferritin expression compared to control cells (20 ngFTL/mg proteins Vs 15,15 ngFTL/mg proteins), only in quercetin-FAC treated cells we observed a Ferritin expression increase compared to control untreated cells (16 ngFTL/mg proteins Vs 24 ngFTL/mg proteins). Results from experiments using endocytosis inhibitors showed that SI absorption in CACO-2 cells is inhibited using Dyngo4a (from 4ngFTL/mg proteins to 0,36 ngFTL/ mg proteisn) while PitStop3 seems to reduce SI absorption in THP1 (from 396 ngFL/mg protein to 199,91 ngFTL/mg proteins) and HepG2 cells (from 26,86 ngFL/mg proteins to 3,93 ngFTL/mg proteins), since ferritin expression significantly decrease only in SI treated cells. Conclusions: endocytosis pathway seems to be involved in SI cellular uptake but this process is regulated in different manner probably due to different cell types. Release experiments showed that cells treated with quercetin could reduce for a negative feedback DMT1 expression as well, affecting iron uptake from cells treated with FAC but not with SI and consequently, if SI is able to bypass commonly iron uptake mechanism, FPN inhibition did not show iron release perturbation from cells treated with SI. Disclosures Brilli: Pharmanutra s.p.a.: Consultancy. Martinelli:Janssen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy; Ariad/Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Tarantino:Pharmanutra s.p.a.: Employment.

scholarly journals NCOA4 Mediates Ferritin Responses to Iron, Erythrophagocytosis, and Hepcidin in Macrophages (P24-056-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Cole Guggisberg ◽  
Moon-Suhn Ryu
Keyword(s):  
Iron Homeostasis ◽  
Primary Source ◽  
Viable Cell ◽  
Iron Chelator ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Anemia Of Chronic Disease ◽  
Cell Counts ◽  
Subsequent Decrease

Abstract Objectives Iron recycled from erythrophagocytosis by macrophages serves as a primary source of systemic iron. NCOA4 mediates ferritin turnover via ferritinophagy. Yet, whether NCOA4 is important in macrophages or erythrophagocytosis-mediated iron recycling remains unclear, and thus was assessed in vitro. Methods J774 cells were employed as an in vitro model of macrophages. Iron studies involved treatments of ferric ammonium citrate (FAC) or an iron chelator, deferoxamine (Dfo). To recapitulate systemic iron recycling and overload, cells were treated with opsonized erythrocytes and minihepcidin, respectively. NCOA4 knock-down was achieved by siRNA transfection. Iron gene responses were measured by qPCR and western analyses, and viable cell counts were colorimetrically determined by CCK8 assays as functional outcomes. Results NCOA4 protein abundance was inversely related to iron availability and ferritin in macrophages. Loss of NCOA4 resulted in impaired ferritin turnover, and led to a reduction in viable cells when combined with iron deficiency. By erythrophagocytosis, a peak in ferritin abundance was observed at 12 h with a subsequent decrease at 24 h. This loss in ferritin was NCOA4-dependent. Minihepcidin caused accumulation of ferritin, along with a repression of NCOA4 in both control and erythrocyte-laden macrophages. Hepcidin activity had no effect on ferritin when NCOA4 was depleted. Conclusions NCOA4 mediates the release of ferritin iron during cellular iron restriction and iron recycling by macrophages. Moreover, our studies suggest that macrophage NCOA4 is integral to systemic iron homeostasis by responding to the iron regulatory hormone, hepcidin. Thus, NCOA4 and ferritinophagy may potentially serve as therapeutic targets for treatments of iron disorders and anemia of chronic disease. Funding Sources Supported by the NIFA, USDA, Hatch project under MIN-18–118 and intramural support to M-S.R.

Chemicals That Stimulate Iron Uptake – A Novel Approach to Treatment of Iron Deficiency,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3180-3180
Author(s):  
Zhen Li
Keyword(s):  
Iron Deficiency ◽  
Small Molecules ◽  
Iron Uptake ◽  
Iron Absorption ◽  
K562 Cells ◽  
Divalent Metal ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Caco2 Cells ◽  
Ferric Ammonium

Abstract 3180 Iron (Fe) is an essential nutrient required for all cells, especially for erythrocyte hemoglobin synthesis which requires absorption of 1–2 mg of iron from the gastrointestinal tract. Iron deficiency as a result of inadequate dietary uptake has multiple consequences including anemia and abnormal neurologic development in children and is a global public health concern. Enterocytes in the duodenum, the site of iron absorption, can extract about 10% of dietary Fe. Nonetheless for numerous reasons simple iron supplementation has not solved the worldwide epidemic of iron deficiency. We hypothesized that small molecules which could potentiate iron uptake into cells would allow enterocytes to absorb an increased amount of dietary iron and could be beneficial in limiting iron deficiency. To identify molecules that would accelerate Fe uptake we used a high through-put screening system in conjunction with a reporter system of K562 cells loaded with the divalent metal chelator calcein whose fluorescence is quenched with chelation of Fe2+. Small molecules that stimulated Fe uptake were defined as causing increased calcein fluorescence quenching compared to Fe alone. K562 cells were exposed to 0.1 μM calcein for 10 minutes, thoroughly washed, and 1 × 105 cells plated into each well of multiple 96-well plates. After equilibration of the plates at 37° C, aliquots of the individual components of an in-house chemical library of ∼12,000 compounds dissolved in DMSO were screened in duplicate or triplicate and fluorescence measurements made at 0 and 30 min after addition of 10 μM FeNH4SO4 in a Synergy IV plate reader. 30 chemicals were identified that stimulated iron-induced quenching of calcein fluorescence. The stimulation was verified by dose response curves and by assaying the effect on non-transferrin bound 55Fe uptake. None of the stimulators were cytotoxic for up to at least 3 days. The lead compound, LS081, had an IC50 = 1.22 ± 0.48 μM for 55Fe uptake in K562 cells compared to controls. LS081 was also used to examine the iron uptake in Caco2 cells grown in bicameral chambers, a model system to study intestinal iron absorption. LS081 significantly increased 55Fe uptake into Caco2 cells with a very rapid influx of 55Fe in the first 5 min after Fe was offered to the apical surface followed by a ∼ 4-fold increased uptake over the next 90 min. 55Fe transport across the basolateral surface into the basal chamber also increased ∼ 4 fold. The increased 55Fe transport in caco2 cells is more prominent at lower pH of 5.5 compare to pH 7.5 suggesting LS081 acted on a common divalent metal uptake pathway. Mice treated with LS081 + ferric ammonium citrate via oral gavage for two weeks significantly increased (p < 0.001 by unpaired t-test compared to ferric ammonium citrate alone) the level of ferritin, the iron storage protein, in the liver, demonstrating the absorption of LS081 from intestinal cells. In summary, using high through-put screening technique we identified small molecules that stimulate iron uptake and could be used as a drug for iron deficiency. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In Vitro Bioaccessibility and Bioavailability of Iron from Mature and Microgreen Fenugreek, Rocket and Broccoli

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1057
Author(s):  
Kholoud K. Khoja ◽  
Amy Buckley ◽  
Mohamad F. Aslam ◽  
Paul A. Sharp ◽  
Gladys O. Latunde-Dada
Keyword(s):  
Iron Deficiency ◽  
Iron Uptake ◽  
Mineral Content ◽  
Microwave Digestion ◽  
Surrogate Marker ◽  
Risk Groups ◽  
Ammonium Citrate ◽  
Iron Nutrition ◽  
Ferric Ammonium Citrate

Iron deficiency is a global epidemic affecting a third of the world’s population. Current efforts are focused on investigating sustainable ways to improve the bioavailability of iron in plant-based diets. Incorporating microgreens into the diet of at-risk groups in populations could be a useful tool in the management and prevention of iron deficiency. This study analysed and compared the mineral content and bioavailability of iron from microgreen and mature vegetables. The mineral content of rocket, broccoli and fenugreek microgreens and their mature counterparts was determined using microwave digestion and ICP-OES. Iron solubility and bioavailability from the vegetables were determined by a simulated gastrointestinal in vitro digestion and subsequent measurement of ferritin in Caco-2 cells as a surrogate marker of iron uptake. Iron contents of mature fenugreek and rocket were significantly higher than those of the microgreens. Mature fenugreek and broccoli showed significantly (p < 0.001) higher bioaccessibility and low-molecular-weight iron than found in the microgreens. Moreover, iron uptake by Caco-2 cells was significantly higher only from fenugreek microgreens than the mature vegetable. While all vegetables except broccoli enhanced FeSO4 uptake, the response to ferric ammonium citrate (FAC) was inhibitory apart from the mature rocket. Ascorbic acid significantly enhanced iron uptake from mature fenugreek and rocket. Microgreen fenugreek may be bred for a higher content of enhancers of iron availability as a strategy to improve iron nutrition in the populace.

scholarly journals CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
Katie Troike ◽  
Erin Mulkearns-Hubert ◽  
Daniel Silver ◽  
James Connor ◽  
Justin Lathia
Keyword(s):  
Tumor Cells ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Tumor Grade ◽  
Hfe Gene ◽  
Iron Release ◽  
Female Patients ◽  
Cellular Iron

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.

scholarly journals Solubility and Impact of Ascorbic Acid on the in vitro Bioavailability of Two Casein-Based Iron Fortificants from Reconstituted Milk

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1836-1836
Author(s):  
Magalie Sabatier ◽  
Joeska Husny ◽  
Marine Nicolas ◽  
Stèphane Dubascoux ◽  
Mary Bodis ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Iron Uptake ◽  
Iron Absorption ◽  
In Vitro Digestion ◽  
Iron Level ◽  
Similar Amount ◽  
Soluble Iron ◽  
Reconstituted Milk ◽  
The Impact

Abstract Objectives The two objectives were 1) to evaluate the solubility of two iron casein complexes (ICCs) under a condition mimicking gastric pH, 2) to evaluate the impact of ascorbic acid (AA) on the in vitro iron absorption of ICCs after incorporation in reconstituted whole milk powder. Methods The in vitro solubility was determined over time after addition of diluted HCl (pH 1.7), ultracentrifugation and measurement of iron appearing in the supernatant by ICP-OES (n = 2). The impact of AA on iron uptake from the Fe compounds in reconstituted milk was determined using the in vitro digestion coupled with the Caco-2 cell model and the measurement of ferritin/total protein produced by the cells (n = 3). The molar ratio of AA to iron of 2 to 1 recommended by the WHO for iron absorption optimization has been tested with an iron level corresponding to 3.3 mg Fe/serving of milk. Ferrous sulfate (FeSO4), the reference compound for iron bioavailability and micronized ferric pyrophosphate (FePP), main salt used for milk fortification were used as references. Results The dissolution test showed a rapid solubilization of iron from the ICCs i.e., &gt;75 ± 19.3% at 5 min and &gt;89 ± 0.3% at 90 min. The kinetics of soluble iron from the complexes were like that from FeSO4. The solubility of FePP was only 37.6 ± 4.7% at 90 min. Without AA, the iron uptake from FeSO4 was lower than expected translating into a relative in vitro bioavailability (iRBA) of FePP and of the two ICCs to FeSO4 of 66, 169 and 215%. This might be explained by a rapid conversion of soluble iron from FeSO4 into Fe3+ and insoluble iron hydroxide when the pH increased from 2 to &gt;7 during in vitro digestion. However, with the addition of AA in the milk, iron uptake by the cells was found to be increased to levels of 341.8 ± 8.9, 124 ± 12.2, 403.1 ± 117.8 and 362.9 ± 36.9 ng ferritin/mg protein for FeSO4, FePP and the two ICCs respectively. This translates into iRBAs to FeSO4 of 36% for FePP and of 118 and 106% for the two ICCs. Conclusions The solubility and the demonstrated impact of AA on Fe uptake suggest that ICCs are absorbed to a similar amount as FeSO4 and thus provide an excellent source of Fe. Funding Sources Société des Produits Nestlé, NPTC Konolfingen, Switzerland.

scholarly journals Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Stefanie Dichtl ◽  
Egon Demetz ◽  
David Haschka ◽  
Piotr Tymoszuk ◽  
Verena Petzer ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Content Type ◽  
Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

scholarly journals Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 970 ◽  
Author(s):  
Jessica Bordini ◽  
Federica Morisi ◽  
Fulvia Cerruti ◽  
Paolo Cascio ◽  
Clara Camaschella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Iron Toxicity ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Ferric Carboxymaltose ◽  
High Dose ◽  
Iron Loading

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies.

scholarly journals Persistence of contamination of hens' egg albumen in vitro with Salmonella serotypes

1992 ◽  
Vol 108 (3) ◽  
pp. 389-396 ◽  
Author(s):  
J. L. Lock ◽  
R. G. Board
Keyword(s):  
Cell Membrane ◽  
Glucose Concentration ◽  
Salmonella Enteritidis ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Egg Albumen ◽  
Ferric Ammonium ◽  
Salmonella Serotypes

SUMMARYA study was made of the persistence of different Salmonella serotypes in hens' egg albumen in vitro at 4, 20 and 30 °C. The majority of serotypes remained viable but did not increase in numbers at 20 and 30 °C for 42 days. At 4 °C many of the serotypes died out.The addition of ferric ammonium citrate on the 42nd day of incubation induced multiplication of organisms incubated at 20 and 30 °C, but not at 4 °C. The pH and glucose concentration of the albumen diminished only when heavy growth occurred.Salmonella enteritidis remained viable on the air cell membrane in vitro for 17 days at 4, 20 and 30 °C. Thirty percent of the organisms also remained motile in albumen for 42 days at 25 °C and up to 5% of the cells remained motile for up to 20 days at 4 °C.

LY2928057, An Antibody Targeting Ferroportin, Is a Potent Inhibitor Of Hepcidin Activity and Increases Iron Mobilization In Normal Cynomolgus Monkeys

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3433-3433 ◽  
Author(s):  
Derrick R Witcher ◽  
Donmienne Leung ◽  
Karen A Hill ◽  
David C De Rosa ◽  
Jianghuai Xu ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Potent Inhibitor ◽  
Peptide Hormone ◽  
Beta Thalassemia ◽  
Iron Release ◽  
Employment Equity ◽  
Hek 293 ◽  
Cynomolgus Monkeys ◽  
Equity Ownership

Abstract Hepcidin, a 25-amino acid peptide hormone which is primarily synthesized and secreted from the liver, is a key regulator of iron homeostasis. It regulates dietary iron absorption, plasma iron concentrations, and tissue iron distribution through interactions with ferroportin, the only known mammalian cellular iron exporter. Hepcidin induces the internalization and subsequent degradation of ferroportin. The reduction in iron release caused by the loss of ferroportin, combined with the continuing demand for iron by erythropoietic precursors, results in a decrease in circulating iron levels. Dysregulation of the hepcidin-ferroportin axis contributes to the pathogenesis of different anemias. Decreased synthesis of hepcidin may cause systemic iron overload in iron-loading anemias such as beta-thalassemia; whereas overproduction of hepcidin may contribute to the development of anemia in inflammatory disorders, malignancies, and chronic kidney disease. LY2928057 is a novel humanized IgG4 monoclonal antibody that binds to human ferroportin with a high affinity, blocks the binding of human hepcidin to ferroportin, and is a potent inhibitor of hepcidin activity in a recombinant ferroportin expressing HEK 293 cell-based assay. In addition, this antibody was able to significantly inhibit hepcidin-induced increase in ferritin levels using Caco-2 cells, a human enterocyte cell line that naturally expresses ferroportin. LY2928057 does not block the efflux of iron from ferroportin, nor does this antibody cause the internalization of this transporter in vitro. Administration of LY2928057 results in a dose dependent increase in serum iron and hepcidin in normal cynomolgus monkeys. LY2928057 may provide therapeutic benefit for patients with hepcidin-related anemia by stabilizing ferroportin located on the cell surface, thus restoring iron export and erythropoiesis. LY2928057 is currently in clinical evaluation. Disclosures: Witcher: Eli Lilly and Company: Employment, Equity Ownership. Leung:Eli Lilly and Company: Employment, Equity Ownership. Hill:Eli Lilly and Company: Employment, Equity Ownership. De Rosa:Eli Lilly and Company: Employment, Equity Ownership. Xu:Eli Lilly and Company: Employment, Equity Ownership. Manetta:Eli Lilly and Company: Employment, Equity Ownership. Wroblewski:Eli Lilly and Company: Employment, Equity Ownership. Benschop:Eli Lilly and Company: Employment, Equity Ownership.

scholarly journals Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6319-6325 ◽  
Author(s):  
Wenjie Chen ◽  
Franklin W. Huang ◽  
Tomasa Barrientos de Renshaw ◽  
Nancy C. Andrews
Keyword(s):  
Skeletal Muscle ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Conditional Knockout ◽  
Dietary Iron ◽  
Iron Release ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Signaling Pathway ◽  
Very High

Abstract Hepcidin, a hormone produced mainly by the liver, has been shown to inhibit both intestinal iron absorption and iron release from macrophages. Hemojuvelin, a glycophosphatidyl inositol–linked membrane protein, acts as a bone morphogenetic protein coreceptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In the present study, we show in mice that loss of hemojuvelin specifically in the liver leads to decreased liver hepcidin production and increased tissue and serum iron levels. Although it does not have any known function outside of the liver, hemojuvelin is expressed at very high levels in cardiac and skeletal muscle. To explore possible roles for hemojuvelin in skeletal muscle, we analyzed conditional knockout mice that lack muscle hemojuvelin. The mutant animals had no apparent phenotypic abnormalities. We found that systemic iron homeostasis and liver hepcidin expression were not affected by loss of hemojuvelin in skeletal muscle regardless of dietary iron content. We conclude that, in spite of its expression pattern, hemojuvelin is primarily important in the liver.

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