Erythroferrone structure, function, and physiology: Iron homeostasis and beyond

Srole, Daniel N.; Ganz, Tomas

doi:10.1002/jcp.30247

Cited by 78 publications

(86 citation statements)

References 63 publications

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“…The main systemic regulators of hepcidin include plasma iron concentrations (mainly through the interaction of diferric transferrin with transferrin receptors TFR1 and TFR2 in the liver), hepatic iron stores, systemic inflammation mainly communicated to hepatocytes by IL-6, and erythroid activity conveyed by the concentrations of the erythroid hormone erythroferrone ( Figure 4 ). The mechanisms were reviewed in recent publications [ 25 , 26 ] and will not be discussed here.…”

Section: Hepcidin Synthesis and Eliminationmentioning

confidence: 99%

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

Nemeth

Ganz

2021

IJMS

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257

151

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Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

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Section: Hepcidin Synthesis and Eliminationmentioning

confidence: 99%

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

Nemeth

Ganz

2021

IJMS

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257

151

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“…AI can occur despite sufficient body iron stores (ferritin) due to the direct actions of hepcidin on ferroportin [ 62 ]. Erythroferrone is a recently discovered hormone that acts as a suppressor of hepcidin and directly links erythropoiesis and iron metabolism [ 63 , 64 ]. During increased erythropoiesis (in response to hemorrhage, for example), erythroblasts release erythroferrone which reduces hepcidin expression, thereby permitting the release of cellular iron from stores as well as increasing iron uptake from the gut [ 63 , 64 ].…”

Section: Does Obesity In Pregnancy Trigger An Inflammatory Response?mentioning

confidence: 99%

“…Erythroferrone is a recently discovered hormone that acts as a suppressor of hepcidin and directly links erythropoiesis and iron metabolism [ 63 , 64 ]. During increased erythropoiesis (in response to hemorrhage, for example), erythroblasts release erythroferrone which reduces hepcidin expression, thereby permitting the release of cellular iron from stores as well as increasing iron uptake from the gut [ 63 , 64 ]. Whether erythroferrone action on hepcidin remains unchanged in inflammatory states or blood volume expansion during pregnancy remains to be established…”

Section: Does Obesity In Pregnancy Trigger An Inflammatory Response?mentioning

confidence: 99%

Are Pregnant Women Who Are Living with Overweight or Obesity at Greater Risk of Developing Iron Deficiency/Anaemia?

et al. 2021

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Low-grade inflammation is often present in people living with obesity. Inflammation can impact iron uptake and metabolism through elevation of hepcidin levels. Obesity is a major public health issue globally, with pregnant women often affected by the condition. Maternal obesity is associated with increased pregnancy risks including iron deficiency (ID) and iron-deficiency anaemia (IDA)—conditions already highly prevalent in pregnant women and their newborns. This comprehensive review assesses whether the inflammatory state induced by obesity could contribute to an increased incidence of ID/IDA in pregnant women and their children. We discuss the challenges in accurate measurement of iron status in the presence of inflammation, and available iron repletion strategies and their effectiveness in pregnant women living with obesity. We suggest that pre-pregnancy obesity and overweight/obese pregnancies carry a greater risk of ID/IDA for the mother during pregnancy and postpartum period, as well as for the baby. We propose iron status and weight gain during pregnancy should be monitored more closely in women who are living with overweight or obesity.

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“…Hepcidin, produced by hepatocytes, is the main regulator of iron homeostasis through the inhibition of ferroportin (Fpn), the only known iron exporter [31]. The inhibition of hepcidin mediated by Erfe allows iron absorption and recirculation, increasing its availability for physiological and pathological processes [29,32]. Besides, and independently of Erfe, hepcidin is regulated by matriptase-2, a transmembrane serine protease encoded by the gene TMPRSS6, whose inactivation by deletion or silencing improves IE in a mouse model of thalassaemia [33][34][35].…”

Section: Iron Metabolism Dysregulationmentioning

confidence: 99%

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

Longo

Piolatto

Ferrero

et al. 2021

IJMS

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β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside.

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Erythroferrone structure, function, and physiology: Iron homeostasis and beyond

Cited by 78 publications

References 63 publications

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

Are Pregnant Women Who Are Living with Overweight or Obesity at Greater Risk of Developing Iron Deficiency/Anaemia?

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

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