-
Molecules (Basel, Switzerland) Apr 2017The peptide hormone hepcidin is a key controller of systemic iron homeostasis, and its expression in the liver is mainly regulated by bone morphogenetic proteins (BMPs),... (Review)
Review
The peptide hormone hepcidin is a key controller of systemic iron homeostasis, and its expression in the liver is mainly regulated by bone morphogenetic proteins (BMPs), which are heparin binding proteins. In fact, heparins are strong suppressors of hepcidin expression in hepatic cell lines that act by inhibiting the phosphorylation of SMAD1/5/8 proteins elicited by the BMPs. The inhibitory effect of heparins has been demonstrated in cells and in mice, where subcutaneous injections of non-anticoagulant heparins inhibited liver hepcidin expression and increased iron bioavailability. The chemical characteristics for high anti-hepcidin activity in vitro and in vivo include the 2O-and 6O-sulfation and a molecular weight above 7 kDa. The most potent heparins have been found to be the super-sulfated ones, active in hepcidin suppression with a molecular weight as low as 4 kDa. Moreover, the alteration of endogenous heparan sulfates has been found to cause a reduction in hepcidin expression in vitro and in vivo, indicating that heparins act by interfering with the interaction between BMPs and components of the complex involved in the activation of the BMP/SMAD1/5/8 pathway. This review summarizes recent findings on the anti-hepcidin activity of heparins and their possible use for the treatment of anemia caused by hepcidin excess, including the anemia of chronic diseases.
Topics: Anemia; Animals; Bone Morphogenetic Protein 6; Bone Morphogenetic Proteins; Gene Expression; Heparin; Heparitin Sulfate; Hepcidins; Homeostasis; Humans; Iron; Liver; Protein Binding
PubMed: 28397746
DOI: 10.3390/molecules22040598 -
Bioscience Reports Dec 2017Red blood cell production (erythropoiesis) is the single largest consumer of iron in the body; this need is satisfied by maintaining a sensitive regulation of iron... (Review)
Review
Red blood cell production (erythropoiesis) is the single largest consumer of iron in the body; this need is satisfied by maintaining a sensitive regulation of iron levels. The level of erythropoietic demand regulates the expression of the iron hormone hepcidin and thus iron absorption. Erythropoiesis-mediated regulation of hepcidin is an area of increasing importance and recent studies have identified a number of potential regulatory proteins. This review summarizes our current knowledge about these candidate erythroid regulators of hepcidin and the relation between transferrin receptors and erythropoiesis.
Topics: Animals; Cell Hypoxia; Erythrocytes; Erythropoiesis; Gene Expression Regulation; Hepcidins; Homeostasis; Humans; Iron
PubMed: 29097483
DOI: 10.1042/BSR20170195 -
British Journal of Haematology Aug 2018Recent years have witnessed impressive advances in our understanding of iron metabolism. A number of studies of iron disorders and of their animal models have provided... (Review)
Review
Recent years have witnessed impressive advances in our understanding of iron metabolism. A number of studies of iron disorders and of their animal models have provided landmark insights into the mechanisms of iron trafficking, distribution and homeostatic regulation, the latter essential to prevent both iron deficiency and iron excess. Our perception of iron metabolism has been completely changed by an improved definition of cellular and systemic iron homeostasis, of the molecular pathogenesis of iron disorders, the fine tuning of the iron hormone hepcidin by activators and inhibitors and the dissection of the components of the hepcidin regulatory pathway. Important for haematology, the crosstalk of erythropoiesis, the most important iron consumer, and the hepcidin pathway has been at least partially clarified. Novel potential biomarkers are available and novel therapeutic targets for iron-related disorders have been tested in murine models. These preclinical studies provided proofs of principle and are laying the ground for clinical trials. Understanding iron control in tissues other than erythropoiesis remains a challenge for the future.
Topics: Animals; Erythropoiesis; Hepcidins; Humans; Iron; Iron Overload; Mice; Signal Transduction
PubMed: 29938779
DOI: 10.1111/bjh.15403 -
Med (New York, N.Y.) Feb 2021How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant...
BACKGROUND
How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear.
METHODS
We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant . We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency.
FINDINGS
We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity.
CONCLUSIONS
Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders.
FUNDING
Medical Research Council, UK.
Topics: Animals; Hepcidins; Humans; Immunity, Humoral; Iron; Iron Deficiencies; Iron Metabolism Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Swine; Vaccination
PubMed: 33665641
DOI: 10.1016/j.medj.2020.10.004 -
ELife Sep 2022The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory...
The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in lipopolysaccharide (LPS)-treated wild type mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wild type animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen to stimulate erroportin mRNA translation. Prolonged LPS treatment eliminated ferroportin mRNA and permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is a critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient when combined with iron depletion.
Topics: Animals; Cation Transport Proteins; Hepcidins; Hormones; Lipopolysaccharides; Mice; RNA, Messenger; Signal Transduction
PubMed: 36066082
DOI: 10.7554/eLife.81332 -
British Journal of Haematology Jun 2021The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin... (Review)
Review
The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin assures the balance of circulating and stored iron levels for multiple physiological processes including oxygen transport and erythropoiesis, while limiting the toxicity of excess iron. The liver is the major site where regulatory signals from iron, erythropoietic drive and inflammation are integrated to control hepcidin production. Pathologically, hepcidin dysregulation by genetic inactivation, ineffective erythropoiesis, or inflammation leads to diseases of iron deficiency or overload such as iron-refractory iron-deficiency anaemia, anaemia of inflammation, iron-loading anaemias and hereditary haemochromatosis. In the present review, we discuss recent insights into the molecular mechanisms governing hepcidin regulation, how these pathways are disrupted in iron disorders, and how this knowledge is being used to develop novel diagnostic and therapeutic strategies.
Topics: Anemia, Iron-Deficiency; Animals; Erythropoiesis; Hemochromatosis; Hepcidins; Humans; Liver
PubMed: 33316086
DOI: 10.1111/bjh.17252 -
Blood Jul 2023Inflammation leads to functional iron deficiency by increasing the expression of the hepatic iron regulatory peptide hepcidin. Inflammation also stimulates fibroblast...
Inflammation leads to functional iron deficiency by increasing the expression of the hepatic iron regulatory peptide hepcidin. Inflammation also stimulates fibroblast growth factor 23 (FGF23) production by increasing both Fgf23 transcription and FGF23 cleavage, which paradoxically leads to excess in C-terminal FGF23 peptides (Cter-FGF23), rather than intact FGF23 (iFGF23) hormone. We determined that the major source of Cter-FGF23 is osteocytes and investigated whether Cter-FGF23 peptides play a direct role in the regulation of hepcidin and iron metabolism in response to acute inflammation. Mice harboring an osteocyte-specific deletion of Fgf23 showed a ∼90% reduction in Cter-FGF23 levels during acute inflammation. Reduction in Cter-FGF23 led to a further decrease in circulating iron in inflamed mice owing to excessive hepcidin production. We observed similar results in mice showing impaired FGF23 cleavage owing to osteocyte-specific deletion of Furin. We next showed that Cter-FGF23 peptides bind members of the bone morphogenetic protein (BMP) family, BMP2 and BMP9, which are established inducers of hepcidin. Coadministration of Cter-FGF23 and BMP2 or BMP9 prevented the increase in Hamp messenger RNA and circulating hepcidin levels induced by BMP2/9, resulting in normal serum iron levels. Finally, injection of Cter-FGF23 in inflamed Fgf23KO mice and genetic overexpression of Cter-Fgf23 in wild type mice also resulted in lower hepcidin and higher circulating iron levels. In conclusion, during inflammation, bone is the major source of Cter-FGF23 secretion, and independently of iFGF23, Cter-FGF23 reduces BMP-induced hepcidin secretion in the liver.
Topics: Animals; Mice; Fibroblast Growth Factors; Hepcidins; Inflammation; Iron; Peptides
PubMed: 37053547
DOI: 10.1182/blood.2022018475 -
Arteriosclerosis, Thrombosis, and... Feb 2019Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron...
Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp/ Ldlr) mice and Hamp/ Ldlr control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp/ Ldlr mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp/ Ldlr mice was considered. Hamp/ Ldlr mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp/ Ldlr mice. Aortic macrophages from Hamp/ Ldlr mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp/ Ldlr mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.
Topics: Animals; Atherosclerosis; Female; Hepcidins; Iron; Macrophages; Male; Mice; Mice, Inbred C57BL; Receptors, LDL
PubMed: 30587002
DOI: 10.1161/ATVBAHA.118.312215 -
Frontiers in Public Health 2022Hepcidin has been identified as a systemic iron-regulatory hormone. Recent studies have suggested that iron metabolism disorders may be involved in the pathogenesis of... (Meta-Analysis)
Meta-Analysis
BACKGROUNDS
Hepcidin has been identified as a systemic iron-regulatory hormone. Recent studies have suggested that iron metabolism disorders may be involved in the pathogenesis of acute respiratory distress syndrome and multiple organ dysfunction in coronavirus disease 2019 (COVID-19).
OBJECTIVES
To re-evaluate the hepcidin-related iron metabolism parameters and explore the relationship between hepcidin-mediated iron dysmetabolism and COVID-19 severity.
METHODS
COVID-19 is classified as mild and moderate as non-severe, severe and critical as severe. A meta-analysis was conducted. Four bibliographic databases were comprehensively searched up to December 31st 2021.
RESULTS
Six unique studies with data from 477 COVID-19 patients were included. Compared to non-severe cases, severe cases had higher hepcidin (standardized mean difference (SMD), -0.39; 95% Confidence Interval (CI) [-0.76, -0.03]; = 0.03) and ferritin (SMD, -0.84; 95% CI [-1.30, -0.38]; = 0.0004). In five out of six studies, a total of 427 patients were tested for serum iron, and there were significant differences in their levels between severe and non-severe cases (SMD, 0.22; 95% CI [0.02, 0.41]; = 0.03). A total of 320 patients from four out of six studies were tested for transferrin saturation, and the statistical difference was not significant (SMD, 0.06; 95% CI [-0.17, 0.28]; = 0.64).
CONCLUSION
Severe COVID-19 cases had higher serum levels of hepcidin and ferritin, and lower serum iron, without significant differences in transferrin saturation. Further studies are needed to verify whether targeting the hepcidin-mediated iron metabolism axis may influence the outcome and treatment of COVID-19.
Topics: COVID-19; Ferritins; Hepcidins; Humans; Iron; Transferrin
PubMed: 35558525
DOI: 10.3389/fpubh.2022.881412 -
Biochemia Medica 2016Hepcidin is a small peptide with a critical role in cellular iron homeostasis, as it regulates utilization of stored iron and antimicrobial defense in inflammation... (Review)
Review
Hepcidin is a small peptide with a critical role in cellular iron homeostasis, as it regulates utilization of stored iron and antimicrobial defense in inflammation (bacterial and fungal). Since it was isolated in 2000, and especially in the last decade, numerous studies aimed to evaluate the clinical use of plasma and urine hepcidin as a marker of anemia, especially anemia of chronic disease and post-transplant anemia (PTA). Hepcidin regulation is delicately tuned by two inflammatory pathways activated by interleukin-6 (IL-6) and bone morphogenic proteins (BMPs) and iron regulated pathway sensitive to circulating transferin-iron (TR-Fe) complex. BMP-mediated pathway and TR-Fe sensitive pathway seem to be connected by hemojuveline, a BMP co-factor that interacts with transferine receptor 2 (TRF2) in cases of high TR-Fe circulatory concentration. In addition to these regulatory mechanisms other regulators and signaling pathways are being extensively researched. Hepcidin has been identified as an important contributor to morbidity and mortality in end stage renal disease (ESRD) but no such association has jet been found in case of PTA. However, there is an association between higher doses of erythropoiesis-stimulating agents (ESA) and mortality in the posttransplant period and the assumption that hepcidin might play a role in ESA resistance in PTA. Thus the review's main goal was to summarize papers published on the association of hepcidin with PTA, give up-to-date information on hepcidin regulation and on potential therapeutics that optimize hepcidin regulation. We also compared the performances of tests for hepcidin determination and reviewed research on immunosuppressants' (IS) effect on hepcidin concentration.
Topics: Amino Acid Sequence; Anemia; Biomarkers; Hepcidins; Humans; Kidney Failure, Chronic; Kidney Transplantation; Molecular Sequence Data; Outcome Assessment, Health Care; Signal Transduction
PubMed: 26981017
DOI: 10.11613/BM.2016.003