The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation
Open accessAbstract
The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency.Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies.Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo.Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations.A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron.The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states.These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders.
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Turpentine-induced hypoferremia is not observed in hepcidin-deficient mice, demonstrating that hepcidin is required for iron sequestration during inflammatory conditions.
“the turpentine-induced hypoferremia was not observed in hepcidin-deficient mice (8), demonstrating that hepcidin is required for iron sequestration during inflammatory conditions”
From IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) · cites this paper as [8]
The results and discussion (p. 1042) report that turpentine lowered serum iron in wild-type mice but not in hepcidin-deficient mice. They establish hepcidin’s role in the inflammatory fall in serum iron, but describe iron sequestration as a proposed mechanism, not one directly demonstrated by that experiment. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHepcidin synthesis is regulated by dietary iron and iron stores, as well as by tissue oxygenation.
“hepcidin synthesis is regulated by dietary iron and iron stores, as well as by tissue oxygenation”
From IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) · cites this paper as [8]
The hypoxia results report that reduced tissue oxygenation downregulated hepcidin gene expression in mice. The anemia results show that iron loading increased expression, and the Discussion links iron deficiency to low expression until stores are repleted. The paper does not show that dietary iron itself regulates hepcidin synthesis; it describes hepcidin regulating dietary iron absorption instead. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHepcidin mRNA expression is decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen.
“decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen”
From IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) · cites this paper as [8]
Turpentine injections increase hepcidin mRNA in mice.
“injections of turpentine increased hepcidin mRNA”
From IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) · cites this paper as [8]
Turpentine injections decrease serum iron in mice.
“decreased serum iron”
From IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) · cites this paper as [8]
Infection and inflammation induce hepcidin production, which lowers plasma iron by inhibiting iron absorption and promoting iron sequestration in macrophages.
“Infection and inflammation induce hepcidin production, driving a decrease in plasma iron concentrations by inhibiting the absorption of iron and promoting the sequestration of iron in macrophages.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [26]
The increase in hepcidin secretion in response to infectious or inflammatory stimuli is responsible for the characteristic hypoferraemia of inflammation.
“The increase in hepcidin secretion in response to infectious or inflammatory stimuli is responsible for the characteristic hypoferraemia of inflammation26,27, which develops within a few hours of a systemic infection or following injection of microbial components or certain cytokines.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [26]
Anaemia and anoxia suppress hepcidin production, so while superoxide production is enhanced by anoxia, more iron is absorbed from the intestine and effluxed into the circulation.
“Strikingly, anaemia and anoxia both suppress hepcidin production [245,339,340] (Fig 3), such that just while superoxide production is being enhanced by the anoxia there is more iron being absorbed from the intestine and effluxed into the circulation.”
A common mechanism of hypoferremia of inflammation is a cytokine-driven increase in hepcidin that downregulates ferroportin and decreases iron flow into extracellular fluid from all sources.
“A common mechanism of hypoferremia of inflammation is a cytokine-driven increase in hepcidin [15] that downregulates ferroportin and thereby decreases iron flow into extracellular fluid from all its sources.”
From Iron and infection (2018) · cites this paper as [15]
Under increased hepcidin, recycled iron is retained in liver and spleen macrophages, and iron absorption is decreased.
“Thus, under the influence of increased concentrations of hepcidin, recycled iron is retained in macrophages of the liver and the spleen, and iron absorption is decreased.”
From Iron and infection (2018) · cites this paper as [15]
Hepcidin expression is inhibited by hypoxia and erythropoiesis.
“Conversely, hepcidin expression is inhibited by hypoxia and erythropoiesis [11,12].”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [11]
The amount of hepcidin mRNA in liver cells is decreased in response to hypoxia and ineffective erythropoiesis and induced in response to treatment with lipopolysaccharide or by inflammation of other etiologies.
“In addition, the amount of hepcidin mRNA in liver cells is decreased in response to hypoxia and ineffective erythropoiesis (overlapping with the response to iron deficiency) 99,105 and induced in response to treatment with lipopolysaccharide or by inflammation of other etiologies.92,99”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [99]
Murine hepcidin mRNA is elevated in response to iron overload and decreased in response to iron deficiency.
“Initially, murine hepcidin mRNA was shown to be elevated in response to iron overload 92 and decreased in response to iron deficiency.99,100”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [99]
Experimental studies in cultured cells, animal models and human subjects have established that hepcidin production is O2-sensitive and involves the HIF pathway.
“Experimental studies in cultured cells, in animal models and in human subjects have established that hepcidin production is O2-sensitive and involves the HIF pathway.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [192]
A study that examined postmortem unfixed frozen brain sections from elderly normal or PD-affected individuals showed that individual neurons from brains of individuals with PD had significantly elevated iron concentrations.
“A study that examined postmortem unfixed frozen brain sections from elderly normal or PD-affected individuals showed that individual neurons from brains of individuals with PD had significantly elevated iron concentrations (220).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [220]
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- Authors
- Nicolas, G., Chauvet, C., Viatte, L., Danan, J. L., Bigard, X., Devaux, I., Beaumont, C., Kahn, A., & Vaulont, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Service de Santé des Armées (FR)
- Inserm (FR)
- Corresponding author
- Vaulont, Sophie
- Venue
- Journal of Clinical Investigation
- Published
- 2002-10-01
- Volume
- 110
- Issue
- 7
- Pages
- 1037-1044
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4243766541
- Cited by
- 1,214
- References
- 14
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 16 · 2023: 36 · 2022: 33 · 2021: 35 · 2020: 63 · 2019: 52 · 2018: 53 · 2017: 55 · 2016: 44 · 2015: 45 · 2014: 71 · 2013: 58 · 2012: 61
- FWCI
- 20.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- hepcidin, iron homeostasis, anemia, hypoxia, inflammation, iron deficiency, iron overload, phlebotomy, turpentine, hepatoma cells, serum iron, reticuloendothelial cells
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