Fetal liver hepcidin secures iron stores in utero

Abstract In the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and recycling, respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harboring a paternally-inherited ubiquitous knock-in of the HAMP-resistant fpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in of fpnC326Y or knockout of the hamp gene. These fetuses had reduced liver iron stores and hemoglobin, and markedly increased FPN in the liver, but not in the placenta. Thus, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is not actively regulated by fetal liver HAMP under normal physiological conditions.

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Fetal liver hepcidin secures iron stores in utero

10.1101/799304 ◽

2019 ◽

Author(s):

Lara Kämmerer ◽

Goran Mohammad ◽

Magda Wolna ◽

Peter A. Robbins ◽

Samira Lakhal-Littleton

Keyword(s):

Iron Overload ◽

Iron Transport ◽

Iron Homeostasis ◽

Iron Absorption ◽

Fetal Liver ◽

In Utero ◽

Liver Iron ◽

Iron Stores ◽

Maternal Iron

AbstractIn the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and recycling respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harbouring a paternally-inherited ubiquitous knock-in of the HAMP-resistant fpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in of fpnC326Y or knockout of the hamp gene. These fetuses had reduced liver iron stores, and markedly increased FPN in the liver, but not in the placenta. Thus, in contrast to the adult, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is permissive rather than regulatory of iron transport.

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Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽

10.1182/blood-2019-129658 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 816-816 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Tomas Ganz ◽

Mary Therese Forsyth ◽

Elizabeta Nemeth ◽

Sherif M. Badawy

Keyword(s):

Gene Therapy ◽

Stem Cell ◽

Iron Overload ◽

Serum Ferritin ◽

Research Funding ◽

Iron Homeostasis ◽

Beta Thalassemia ◽

Ineffective Erythropoiesis ◽

Liver Iron ◽

Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

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RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and Decreases Iron Overload in Hfe−/− Mice

Blood ◽

10.1182/blood.v120.21.1018.1018 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1018-1018

Author(s):

Paul J Schmidt ◽

Anoop K Sendamarai ◽

Ivanka Toudjarska ◽

Tim Racie ◽

Jim S Butler ◽

...

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Iron Absorption ◽

Disease Phenotype ◽

Ineffective Erythropoiesis ◽

Employment Equity ◽

Liver Iron ◽

Secondary Iron Overload ◽

Equity Ownership ◽

Low Levels

Abstract Abstract 1018 β-Thalassemia intermedia (TI), an inherited hemoglobinopathy caused by partial loss of β-globin synthesis, is characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis as well as secondary iron overload. Hereditary hemochromatosis (HH) is most frequently caused by mutations in HFE and is marked by excess uptake of dietary iron with concomitant tissue iron overload. In both diseases, increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (encoded by Hamp1). The membrane serine protease Matriptase-2 (encoded by Tmprss6) attenuates BMP-mediated Hamp1 induction by cleaving the BMP co-receptor, hemojuvelin. Previously, it has been shown that elevating Hamp1 expression by genetic inactivation of Tmprss6 reduces disease severity in the Hbbth3/+ mouse model of TI and prevents iron overload in Hfe−/− mice. Therefore, a therapeutic approach comprising specific inhibition of Tmprss6 could prove efficacious in TI and HH. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to >80% inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ and Hfe−/− mice with concomitant >2-fold elevation in Hamp1 expression. In the TI model, Tmprss6 silencing leads to ∼30% reductions in serum iron and non-heme liver iron. In Hfe−/− mice, serum iron and non-heme liver iron are similarly reduced, and Perls staining of peri-portal iron is diminished. Remarkably, the partial iron restriction induced by Tmprss6 inhibition in Hbbth3/+ mice leads to dramatic improvements in the hematological aspects of the disease phenotype: the severity of the anemia is decreased as evidenced by an approximately 1 g/dL increase in total hemoglobin and a 50% decrease in circulating erythropoietin levels. As in the human disease, Hbbth3/+ mice exhibit the hallmarks of ineffective erythropoiesis including splenomegaly, decreased erythrocyte survival and marked reticulocytosis. Treatment with LNP formulated Tmprss6 siRNA leads to a dramatic 2–3 fold decrease in spleen size, a 3–4 fold decrease in reticulocyte counts and a >7-day increase in RBC half-life. Histological analysis of spleens from Tmprss6 siRNA treated animals demonstrates restoration of normal splenic architecture, as well as a reduction in the number of Tfr1-positive erythrocyte precursors in the spleen. Furthermore, as evidenced by the near normalization of blood smears, the overall quality of erythropoiesis in treated animals is vastly improved. Taken together, these data demonstrate that RNAi-mediated silencing of liver Tmprss6 elevates Hamp1 expression and reduces iron overload in both TI and HH model mice. More significantly, Tmprss6 siRNA treatment ameliorates all aspects of the disease phenotype in the TI mouse model. These results support the development of an RNAi therapeutic targeting TMPRSS6 for the treatment of TI, HH and potentially other disorders characterized by excess iron absorption due to physiologically inappropriately low levels of hepcidin. Disclosures: Racie: Alnylam Pharmaceuticals: Employment. Butler:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Dietary Supplementation with Genistein Increases Hepcidin Expression in Wild Type Mice

Blood ◽

10.1182/blood.v120.21.3208.3208 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3208-3208

Author(s):

Aileen W. Zhen ◽

Josephine Volovetz ◽

Paula G. Fraenkel

Keyword(s):

Iron Overload ◽

Iron Content ◽

Iron Absorption ◽

Small Scale ◽

Iron Release ◽

Liver Iron ◽

Transcript Levels ◽

Intestinal Iron Absorption ◽

Hepcidin Expression ◽

Liver Iron Content

Abstract Abstract 3208 Iron overload is an important cause of morbidity and death in patients with hemoglobinopathies, transfusion-dependent anemias, and hereditary hemochromatosis. As humans have no means of excreting iron, regulation of iron homeostasis depends on limiting intestinal iron absorption and optimizing iron release from macrophages to developing erythrocytes. Hepcidin, a peptide hormone produced in the liver, modulates intestinal iron absorption and macrophage iron release via effects on ferroportin. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. We conducted a small-scale chemical screen and found that the isoflavone genistein, a major dietary component of soybeans, enhanced Hepcidin transcript levels in zebrafish embryos. Furthermore genistein treatment increased Hepcidin transcript levels and Hepcidin promoter activity in human hepatocytes (HepG2 cells) in a Stat3 and Smad4-dependent manner. To evaluate genistein's effect in a mammalian model, we placed groups of 4 four-week old male C57BL/6 mice on an iron-sufficient, low soy diet (AIN93G containing 35 mg of iron/kg) supplemented with 0, 250, or 500 mg of genistein per kg of food for 7 weeks, and then sacrificed the animals for analysis. Plasma genistein levels (mean±SE) at the time of sacrifice were 0.015±0.015, 0.52±0.173, and 2.07±0.65 micromolar, respectively. Compared to mice not treated with genistein, the 250 mg/kg dose produced a significant increase in hepatic Hepcidin (HAMP1) transcript levels (1.49±0.10 vs 0.93±0.10, p=0.01), while the 500 mg/kg dose did not. Although liver iron content, spleen iron content, and weight gain were not significantly different among the groups, the ratio of Hepcidin expression to liver iron content was significantly increased in the animals treated with genistein 250 mg/kg compared to controls (0.013±0.0009 vs 0.0074±0.00068, p=0.0068). In conclusion, genistein is the first orally administered small molecule experimental drug shown to increase Hepcidin transcript levels in vivo. Future experiments will evaluate the effects of genistein on genetic models of iron overload syndromes. Disclosures: No relevant conflicts of interest to declare.

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Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6

Blood ◽

10.1182/blood-2010-07-295147 ◽

2011 ◽

Vol 117 (2) ◽

pp. 647-650 ◽

Cited By ~ 21

Author(s):

Anne Lenoir ◽

Jean-Christophe Deschemin ◽

Léon Kautz ◽

Andrew J. Ramsay ◽

Marie-Paule Roth ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Serine Protease ◽

Iron Deficiency Anemia ◽

Iron Homeostasis ◽

Deficiency Anemia ◽

Hepatic Iron ◽

Master Regulator ◽

Liver Iron ◽

The Relationship

Abstract Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6−/− mice (characterized by increased hepcidin levels and anemia) and Bmp6−/− mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6−/− mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.

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Duodenal nonheme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out

Blood ◽

10.1182/blood-2002-10-3112 ◽

2003 ◽

Vol 101 (8) ◽

pp. 3316-3318 ◽

Cited By ~ 8

Author(s):

Robert J. Simpson ◽

Edward S. Debnam ◽

Abas H. Laftah ◽

Nita Solanky ◽

Nick Beaumont ◽

...

Keyword(s):

Iron Content ◽

Iron Absorption ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Nonheme Iron ◽

Hfe Gene ◽

Liver Iron ◽

Knock Out ◽

Iron Stores ◽

Knock Out Mice

Abstract Hereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P < .001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P < .001).

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Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis

Blood ◽

10.1182/blood-2021-153902 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 757-757

Author(s):

Veena Sangkhae ◽

Vivian Yu ◽

Richard Coffey ◽

Tomas Ganz ◽

Elizabeta Nemeth

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Minor Role ◽

Iron Availability ◽

Liver Iron ◽

Iron Deficient ◽

Embryo Liver ◽

A Minor ◽

Maternal Iron ◽

Iron Concentrations

Abstract Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

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An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

eLife ◽

10.7554/elife.19804 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 63

Author(s):

Samira Lakhal-Littleton ◽

Magda Wolna ◽

Yu Jin Chung ◽

Helen C Christian ◽

Lisa C Heather ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Iron Homeostasis ◽

Iron Absorption ◽

Metabolic Dysfunction ◽

Cardiac Iron ◽

Cardiac Iron Overload ◽

A Cell ◽

The Brain ◽

Specific Deletion

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.

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Modulation of the HIF2-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis

Blood ◽

10.1182/blood.2021013452 ◽

2022 ◽

Author(s):

Nupur K Das ◽

Chesta Jain ◽

Amanda D. Sankar ◽

Andrew J Schwartz ◽

Naiara Santana-Codina ◽

...

Keyword(s):

Iron Deficiency ◽

Mouse Model ◽

Iron Overload ◽

Iron Homeostasis ◽

Iron Absorption ◽

Hypoxia Inducible Factor ◽

Whole Body ◽

Deficiency Anemia ◽

Null Mouse ◽

Intestinal Iron Absorption

Intestinal iron absorption is activated during increased systemic iron demand. The best-studied example is iron-deficiency anemia, which increases intestinal iron absorption. Interestingly, the intestinal response to anemia is very similar to that of iron overload disorders, as both the conditions activate a transcriptional program that leads to a hyperabsorption of iron via the transcription factor hypoxia-inducible factor (HIF)2a. However, pathways to selectively target intestinal-mediated iron overload remain unknown. Nuclear receptor co-activator 4 (NCOA4) is a critical cargo receptor for autophagic breakdown of ferritin (FTN) and subsequent release of iron, in a process termed ferritinophagy. Our work demonstrates that NCOA4-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF2a. To demonstrate the importance of intestinal HIF2a/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were generated and assessed. These analyses revealed that the intestinal and systemic response to iron deficiency was not altered following disruption of intestinal NCOA4. However, in a mouse model of hemochromatosis, ablation of intestinal NCOA4 was protective against iron overload. Therefore, NCOA4 can be selectively targeted for the management of iron overload disorders without disrupting the physiological processes involved in the response to systemic iron deficiency.

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Serum Ferritin a Predictor of Iron Overload in Patients with Thalassemia and Sickle Cell Disease?.

Blood ◽

10.1182/blood.v104.11.3789.3789 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3789-3789 ◽

Cited By ~ 1

Author(s):

Zahra Pakbaz ◽

Roland Fischer ◽

Richard Gamino ◽

Ellen B. Fung ◽

Paul Harmatz ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Iron Concentration ◽

Cell Disease ◽

Liver Iron Concentration ◽

Liver Iron ◽

Iron Stores ◽

Significant Difference

Abstract Introduction: Monitoring iron overload by serum ferritin in patients with hemosiderosis is still a routine practice although its limitations are widely studied and well known. Using non-invasive liver iron assessment by quantitative MRI or by biomagnetic liver susceptometry (BLS) with SQUID biomagnetometers would be the better alternative, however, these methods are available at only a few centers worldwide. Objective: To determine the relationship between serum ferritin (SF) and liver iron concentration (LIC), measured by BLS at CHRCO, in patients with different types of hemosiderosis. Methods and Patients: A total of 97 patients with thalassemia (TM: 3 to 52 y, 54% females) and 39 patients with sickle cell disease (SCD: 5 to 49 y, 60% female) were prospectively assessed for LIC and SF. Both tests were performed within 2 weeks of each other. Most patients with TM and SCD were chronically transfused, while 10 b-thalassemia intermedia (TI), 5 HbE/β-thalassemia (HbE), and 5 SCD patients were not on transfusion programs. LIC was measured by LTc SQUID biosusceptometer system (Ferritometer®, Model 5700, Tristan Technologies, San Diego, USA) under the standardized Hamburg-Torino-Oakland protocol. A non-parametric test (U-test) was utilized to analyze differences between SF and LIC data. Results: In chronically transfused TM and SCD patients, the median SF and LIC were very similar (Table I). In TI&HbE patients, ferritin results were disproportionately low with respect to LIC. In order to improve prediction of iron stores by SF, the SF/LIC ratio was calculated. There was a significant difference between the median ratios of the two groups of transfused and non- transfused thalassemia patients, 0.82 vs. 0.32 [μg/l]/[μg/gliver], respectively (p < 0.01). In SCD patients the ratio is significantly (p < 0.01) higher. Conclusion: Present data confirm ferritin to be a poor predictor of liver iron stores both in sickle cell disease and thalassemia. Relying only on ferritin to monitor iron overload in patients with hemosiderosis can be misleading, especially, in sickle cell disease and non-transfused thalassemia patients. Taking into account disease specific ferritin-LIC relations, could improve the prediction of iron stores. However, assessment of liver iron stores is the ultimate method to initiate and adjust chelation treatment in order to avoid progressive organ injury. Table I. Median values and ranges ( − ) of serum ferritin (SF) and liver iron concentration (LIC) in transfused (Tx) and non-transfused (non-Tx) hemosiderosis patients. Patient group n SF μg/l] LIC [mg/gliver ] SF:LIC Thalassemia Tx 82 1721 (209–8867) 3424 (364–7570) 0.82 (0.3–1.8) TI &HbE non-Tx 15 766 (52–2681) 2174 (226–5498) 0.32 (0.1–1.4) SCD Tx 34 2757 (400–9138) 1941 (518–6670) 1.2 (0.6–3.3)

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