Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.

Download Full-text

Molecular mechanisms of normal iron homeostasis

Hematology ◽

10.1182/asheducation-2009.1.207 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 207-214 ◽

Cited By ~ 70

Author(s):

An-Sheng Zhang ◽

Caroline A. Enns

Keyword(s):

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Absorption ◽

Hypoxia Inducible Factor ◽

Bmp Signaling ◽

Control Mechanisms ◽

Iron Regulatory Proteins ◽

Hepcidin Expression ◽

Cellular Iron ◽

Morphogenetic Protein

Abstract Humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Dietary iron absorption is regulated locally by hypoxia inducible factor (HIF) signaling and iron-regulatory proteins (IRPs) in enterocytes and systematically by hepatic hepcidin, the central iron regulatory hormone. Hepcidin not only controls the rate of iron absorption but also determines iron mobilization from stores through negatively modulating the function of ferroportin, the only identified cellular iron exporter to date. The regulation of hepatic hepcidin is accomplished by the coordinated activity of multiple proteins through different signaling pathways. Recent studies have greatly expanded the knowledge in the understanding of hepcidin expression and regulation by the bone morphogenetic protein (BMP) signaling, the erythroid factors, and inflammation. In this review, we mainly focus on the roles of recently identified proteins in the regulation of iron homeostasis.

Download Full-text

Role of Dietary Flavonoids in Iron Homeostasis

Pharmaceuticals ◽

10.3390/ph12030119 ◽

2019 ◽

Vol 12 (3) ◽

pp. 119 ◽

Cited By ~ 2

Author(s):

Marija Lesjak ◽

Surjit K. S. Srai

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Iron Absorption ◽

Therapeutic Potential ◽

State Of The Art ◽

Iron Status ◽

Dietary Factors ◽

The Body ◽

Dietary Flavonoids

Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying dietary iron absorption. Several dietary factors, such as flavonoids, are known to greatly affect iron absorption. Recent evidence suggests that flavonoids can affect iron status by regulating expression and activity of proteins involved the systemic regulation of iron metabolism and iron absorption. We provide an overview of the links between different dietary flavonoids and iron homeostasis together with the mechanism of flavonoids effect on iron metabolism. In addition, we also discuss the clinical relevance of state-of-the-art knowledge regarding therapeutic potential that flavonoids may have for conditions that are low in iron such as anaemia or iron overload diseases.

Download Full-text

The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions

Blood ◽

10.1182/blood-2012-11-427765 ◽

2013 ◽

Vol 122 (6) ◽

pp. 885-892 ◽

Cited By ~ 55

Author(s):

Maria Mastrogiannaki ◽

Pavle Matak ◽

Carole Peyssonnaux

Keyword(s):

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Absorption ◽

Hypoxia Inducible Factor ◽

Therapeutic Strategies ◽

The Past ◽

Pathological Conditions ◽

Per Se ◽

Key Genes

Abstract Although earlier, seminal studies demonstrated that the gut per se has the intrinsic ability to regulate the rates of iron absorption, the spotlight in the past decade has been placed on the systemic regulation of iron homeostasis by the hepatic hormone hepcidin and the molecular mechanisms that regulate its expression. Recently, however, attention has returned to the gut based on the finding that hypoxia inducible factor-2 (HIF-2α) regulates the expression of key genes that contribute to iron absorption. Here we review the current understanding of the molecular mechanisms that regulate iron homeostasis in the gut by focusing on the role of HIF-2 under physiological steady-state conditions and in the pathogenesis of iron-related diseases. We also discuss implications for adapting HIF-2–based therapeutic strategies in iron-related pathological conditions.

Download Full-text

Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism

Annals of Nutrition and Metabolism ◽

10.1159/000480743 ◽

2017 ◽

Vol 71 (Suppl. 3) ◽

pp. 40-48 ◽

Cited By ~ 12

Author(s):

Andrew M. Prentice

Keyword(s):

Iron Overload ◽

Molecular Mechanisms ◽

Iron Absorption ◽

Iron Status ◽

Clinical Implications ◽

Pharmaceutical Companies ◽

Dietary Iron ◽

Dietary Interventions ◽

Hepcidin Expression ◽

Fine Control

The fact that humans must balance their need for iron against its potential for causing harm has been known for several centuries, but the molecular mechanisms by which we achieve this feat have only been revealed in the last 2 decades. Chief amongst these is the discovery of the master-regulatory liver-derived hormone hepcidin. By switching off ferroportin in enterocytes and macrophages, hepcidin exerts fine control over both iron absorption and its distribution among tissues. Hepcidin expression is downregulated by low iron status and active erythropoiesis and upregulated by iron overload and infection and/or inflammation. The latter mechanism explains the etiology of the anemia of chronic infection. Pharmaceutical companies are actively developing hepcidin agonists and antagonists to combat iron overload and anemia, respectively. In a global health context the discovery of hepcidin shines a new light on the world's most prevalent micronutrient problem; iron deficiency and its consequent anemia. It is now apparent that humans are not poorly designed to absorb dietary iron, but rather are exerting a tonic downregulation of iron absorption to protect themselves against infection. These new insights suggest that interventions to reduce infections and inflammation will be at least as effective as dietary interventions and that the latter will not succeed without the former.

Download Full-text

The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

Russian Military Medical Academy Reports ◽

10.17816/rmmar83609 ◽

2021 ◽

Vol 40 (4) ◽

pp. 13-24

Author(s):

Igor V. Litvinenko ◽

Igor V. Krasakov

Keyword(s):

Nervous System ◽

Neurodegenerative Diseases ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Brain Structures ◽

Pathological Process ◽

Parkinsons Disease ◽

Neurodegenerative Process ◽

Coronavirus Infection

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

Download Full-text

Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide

Blood ◽

10.1182/blood.v95.1.189 ◽

2000 ◽

Vol 95 (1) ◽

pp. 189-197 ◽

Cited By ~ 292

Author(s):

Hideo Kimura ◽

Alessandro Weisz ◽

Yukiko Kurashima ◽

Kouichi Hashimoto ◽

Tsutomu Ogura ◽

...

Keyword(s):

Nitric Oxide ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Hypoxia Inducible Factor ◽

Vascular Endothelial ◽

Hypoxia Response Element ◽

Response Element ◽

Hypoxia Response ◽

Hypoxia Inducible Factor 1 ◽

Endothelial Growth Factor

Abstract Nitric oxide (NO) regulates production of vascular endothelial growth factor (VEGF) by normal and transformed cells. We demonstrate that NO donors may up-regulate the activity of the human VEGF promoter in normoxic human glioblastoma and hepatoma cells independent of a cyclic guanosine monophosphate–mediated pathway. Deletion and mutation analysis of the VEGF promoter indicates that the NO-responsive cis-elements are the hypoxia-inducible factor-1 (HIF-1) binding site and an adjacent ancillary sequence that is located immediately downstream within the hypoxia-response element (HRE). This work demonstrates that the HRE of this promoter is the primary target of NO. In addition, VEGF gene regulation by NO, as well as by hypoxia, is potentiated by the AP-1 element of the gene. Our study also reveals that NO and hypoxia induce an increase in HIF-1 binding activity and HIF-1 protein levels, both in the nucleus and the whole cell. These results suggest that there are common features of the NO and hypoxic pathways of VEGF induction, while in part, NO mediates gene transcription by a mechanism distinct from hypoxia. This is demonstrated by a difference in sensitivity to guanylate cyclase inhibitors and a different pattern of HIF-1 binding. These results show that there is a primary role for NO in the control of VEGF synthesis and in cell adaptations to hypoxia. (Blood. 2000;95:189-197)

Download Full-text

Iron age: novel targets for iron overload

Hematology ◽

10.1182/asheducation-2014.1.216 ◽

2014 ◽

Vol 2014 (1) ◽

pp. 216-221 ◽

Cited By ~ 9

Author(s):

Carla Casu ◽

Stefano Rivella

Keyword(s):

Iron Overload ◽

Iron Age ◽

Iron Metabolism ◽

Iron Absorption ◽

Hereditary Hemochromatosis ◽

Therapeutic Approaches ◽

Hepcidin Expression ◽

Beneficial Effects ◽

Excess Iron ◽

Major Factors

Abstract Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

Download Full-text

Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽

10.1128/mbio.02624-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Stefanie Dichtl ◽

Egon Demetz ◽

David Haschka ◽

Piotr Tymoszuk ◽

Verena Petzer ◽

...

Keyword(s):

Bacterial Growth ◽

Iron Uptake ◽

Iron Homeostasis ◽

Iron Acquisition ◽

Lipocalin 2 ◽

Intracellular Iron ◽

Content Type ◽

Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

Download Full-text

Physiologic systemic iron metabolism in mice deficient for duodenal Hfe

Blood ◽

10.1182/blood-2006-07-036186 ◽

2007 ◽

Vol 109 (10) ◽

pp. 4511-4517 ◽

Cited By ~ 57

Author(s):

Maja Vujic Spasic ◽

Judit Kiss ◽

Thomas Herrmann ◽

Regina Kessler ◽

Jens Stolte ◽

...

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Iron Absorption ◽

Binding Capacity ◽

Hereditary Hemochromatosis ◽

Direct Interaction ◽

Hfe Gene ◽

Hepatic Iron ◽

Primary Role ◽

Genes Encoding

Abstract Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.

Download Full-text

Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle

Blood ◽

10.1182/blood-2006-08-040006 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4724-4731 ◽

Cited By ~ 79

Author(s):

Paul Robach ◽

Gaetano Cairo ◽

Cecilia Gelfi ◽

Francesca Bernuzzi ◽

Henriette Pilegaard ◽

...

Keyword(s):

Skeletal Muscle ◽

Iron Content ◽

Iron Homeostasis ◽

Iron Acquisition ◽

Hypoxia Inducible Factor ◽

Hemoglobin Concentration ◽

Oxygen Binding ◽

Mrna Levels ◽

Iron Regulatory Proteins ◽

Related Proteins

Abstract Iron is essential for oxygen transport because it is incorporated in the heme of the oxygen-binding proteins hemoglobin and myoglobin. An interaction between iron homeostasis and oxygen regulation is further suggested during hypoxia, in which hemoglobin and myoglobin syntheses have been reported to increase. This study gives new insights into the changes in iron content and iron-oxygen interactions during enhanced erythropoiesis by simultaneously analyzing blood and muscle samples in humans exposed to 7 to 9 days of high altitude hypoxia (HA). HA up-regulates iron acquisition by erythroid cells, mobilizes body iron, and increases hemoglobin concentration. However, contrary to our hypothesis that muscle iron proteins and myoglobin would also be up-regulated during HA, this study shows that HA lowers myoglobin expression by 35% and down-regulates iron-related proteins in skeletal muscle, as evidenced by decreases in L-ferritin (43%), transferrin receptor (TfR; 50%), and total iron content (37%). This parallel decrease in L-ferritin and TfR in HA occurs independently of increased hypoxia-inducible factor 1 (HIF-1) mRNA levels and unchanged binding activity of iron regulatory proteins, but concurrently with increased ferroportin mRNA levels, suggesting enhanced iron export. Thus, in HA, the elevated iron requirement associated with enhanced erythropoiesis presumably elicits iron mobilization and myoglobin down-modulation, suggesting an altered muscle oxygen homeostasis.

Download Full-text