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

Blood ◽  
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.

scholarly journals Intestinal ferritinophagy is regulated by HIF-2α and is essential for systemic iron homeostasis

2020 ◽  
Author(s):  
Nupur K Das ◽  
Amanda Sankar ◽  
Andrew J Schwartz ◽  
Sumeet Solanki ◽  
Xiaoya Ma ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Whole Body ◽  
Null Mouse ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Sequestration

AbstractIron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2α regulates over 90% of all transcripts induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2α. Duodenal NCOA4 expression is regulated by HIF-2α during high systemic iron demands. Moreover, overexpression of intestinal HIF-2α is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2α target. To demonstrate the importance of intestinal HIF-2α/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

scholarly journals Mechanistic and regulatory aspects of intestinal iron absorption

2014 ◽  
Vol 307 (4) ◽  
pp. G397-G409 ◽  
Author(s):  
Sukru Gulec ◽  
Gregory J. Anderson ◽  
James F. Collins
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Whole Body ◽  
Deficiency Anemia ◽  
Inherited Disorders ◽  
Intestinal Iron Absorption ◽  
Body Iron ◽  
Proximal Small Bowel

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.

Iron Homeostasis and Disorders in Dogs and Cats: A Review

2011 ◽  
Vol 47 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Jennifer L. McCown ◽  
Andrew J. Specht
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Essential Element ◽  
The Body ◽  
Deficiency Anemia ◽  
Enzyme Systems ◽  
Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

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

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 647-650 ◽  
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.

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

eLife ◽  
2016 ◽  
Vol 5 ◽  
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.

An Essential Role For Transferrin Receptor 2 In Erythropoiesis During Iron Restriction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 429-429
Author(s):  
Daniel F Wallace ◽  
Cameron J McDonald ◽  
Eriza S Secondes ◽  
Lesa Ostini ◽  
Gautam Rishi ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Deficiency Anemia ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Erythroid Cells ◽  
Iron Restriction ◽  
Extramedullary Erythropoiesis

Abstract Iron deficiency and iron overload are common clinical conditions that impact on the health and wellbeing of up to 30% of the world’s population. Understanding mechanisms regulating iron homeostasis will provide improved strategies for treating these disorders. The liver-expressed proteins matriptase-2 (encoded by TMPRSS6), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis by regulating expression of the iron regulatory hormone hepcidin. Mutations in TMPRSS6 lead to iron refractory iron deficiency anemia, whereas mutations in HFE and TFR2 lead to the iron overload disorder hereditary hemochromatosis. To elucidate the competing roles of these hepcidin regulators, we created mice lacking matriptase-2, Hfe and Tfr2. Tmprss6 -/-/Hfe-/-/Tfr2-/- mice had iron deficiency anemia resulting from hepatic hepcidin over-expression and activation of Smad1/5/8, indicating that matriptase-2 predominates over Hfe and Tfr2 in hepcidin regulation. Surprisingly, this anemia was more severe than in the Tmprss6-/- mice, demonstrated by more extensive alopecia, lower hematocrit and significant extramedullary erythropoiesis in the spleen. There was increased expression of erythroid-specific genes in the spleens of Tmprss6-/-/Hfe-/-/Tfr2-/- mice, consistent with the extramedullary erythropoiesis. Expression of Tfr2 but not Hfe in the spleen was increased in the Tmprss6-/- mice compared to wild type and correlated with the expression of erythroid genes, suggesting that Tfr2 is expressed in erythroid cells. Further analysis of gene expression in the bone marrow suggests that the loss of Tfr2 in the erythroid cells of Tmprss6-/-/Hfe-/-/Tfr2-/- mice causes a delay in the differentiation process leading to a more severe phenotype. In conclusion, our results indicate that Hfe and Tfr2 act upstream of matriptase-2 in hepcidin regulation or in a way that is overridden when matriptase-2 is deleted. These results indicate that inhibition of matriptase-2 would be useful in the treatment of iron overload conditions such as hereditary hemochromatosis. We have also identified a novel role for Tfr2 in erythroid differentiation that is separate from its canonical role as a regulator of iron homeostasis in the liver. This important role of Tfr2 in erythropoiesis only becomes apparent during conditions of iron restriction. Our results provide novel insights into mechanisms regulating and linking iron homeostasis and erythropoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular Mechanisms Regulating Hepcidin Revealed by Hepcidin Disorders

2011 ◽  
Vol 11 ◽  
pp. 1357-1366 ◽  
Author(s):  
Clara Camaschella ◽  
Laura Silvestri
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Transcriptional Control ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Human Life ◽  
Genetic Diseases ◽  
The Body ◽  
Deficiency Anemia ◽  
Iron Regulatory Proteins

Iron is essential for human life, but toxic if present in excess. To avoid iron overload and maintain iron homeostasis, all cells are able to regulate their iron content through the post-transcriptional control of iron genes operated by the cytosolic iron regulatory proteins that interact with iron responsive elements on iron gene mRNA. At the systemic level, iron homeostasis is regulated by the liver peptide hepcidin. Disruption of these regulatory loops leads to genetic diseases characterized by iron deficiency (iron-refractory iron-deficiency anemia) or iron overload (hemochromatosis). Alterations of the same systems are also found in acquired disorders, such as iron-loading anemias characterized by ineffective erythropoiesis and anemia of chronic diseases (ACD) associated with common inflammatory conditions. In ACD, iron is present in the body, but maldistributed, being deficient for erythropoiesis, but sequestered in macrophages. Studies of the hepcidin regulation by iron and inflammatory cytokines are revealing new pathways that might become targets of new therapeutic intervention in iron disorders.

scholarly journals The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 538-542 ◽  
Author(s):  
Tomas Ganz ◽  
Elizabeta Nemeth
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Therapeutic Target ◽  
Iron Homeostasis ◽  
Kidney Diseases ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Therapeutic Targeting ◽  
Chronic Kidney Diseases

Abstract The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed.

scholarly journals A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Steven Bell ◽  
◽  
Andreas S. Rigas ◽  
Magnus K. Magnusson ◽  
Egil Ferkingstad ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Meta Analysis ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Independent Sequence ◽  
Genome Wide ◽  
A Genome

AbstractIron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

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