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1
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Guo Q, Qian C, Wang X, Qian ZM. Transferrin receptors. Exp Mol Med 2025; 57:724-732. [PMID: 40263550 PMCID: PMC12045970 DOI: 10.1038/s12276-025-01436-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/17/2025] [Indexed: 04/24/2025] Open
Abstract
The transferrin receptor (TfR) is one of the key proteins involved in cellular iron uptake. TfR-mediated endocytosis of transferrin-bound iron is the major pathway for iron acquisition by most cells in the body. Over the past three decades, the studies on TfR have made significant progress, and also, our knowledge on cell iron uptake has greatly been improved. Here we focus on recent advances in the studies on TfR and a brief discussion of the structures and functions of four different types of TfR, namely TfR1 (transferrin receptor 1), TfR2 (transferrin receptor 2), TfR3 (glyceraldehyde-3-phosphate dehydrogenase) and TfR4 (cubilin). These proteins work in different cells or organs and at different times, ensuring that cells and tissues get the iron they need. Their normal expression and function are fundamental to the body's iron homeostasis.
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Affiliation(s)
- Qian Guo
- Laboratory of Drug Delivery, School of Medicine, Shanghai University, Shanghai, China.
| | - Christopher Qian
- School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Xinyu Wang
- Laboratory of Drug Delivery, School of Medicine, Shanghai University, Shanghai, China
| | - Zhong-Ming Qian
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
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2
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Li Y, Liu C, Fang B, Chen X, Wang K, Xin H, Wang K, Yang SM. Ferroptosis, a therapeutic target for cardiovascular diseases, neurodegenerative diseases and cancer. J Transl Med 2024; 22:1137. [PMID: 39710702 DOI: 10.1186/s12967-024-05881-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/24/2024] Open
Abstract
The identification of ferroptosis represents a pivotal advancement in the field of cell death research, revealing an entirely novel mechanism of cellular demise and offering new insights into the initiation, progression, and therapeutic management of various diseases. Ferroptosis is predominantly induced by intracellular iron accumulation, lipid peroxidation, or impairments in the antioxidant defense system, culminating in membrane rupture and consequent cell death. Studies have associated ferroptosis with a wide range of diseases, and by enhancing our comprehension of its underlying mechanisms, we can formulate innovative therapeutic strategies, thereby providing renewed hope for patients.
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Affiliation(s)
- Yinghui Li
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Cuiyun Liu
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Bo Fang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Xinzhe Chen
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Kai Wang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Hui Xin
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266021, China.
| | - Kun Wang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China.
| | - Su-Min Yang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China.
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3
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Xu P, Wong RSM, Yan X. Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents. Br J Pharmacol 2024; 181:2833-2850. [PMID: 38653449 DOI: 10.1111/bph.16396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 03/15/2024] [Accepted: 03/17/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND AND PURPOSE Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. KEY RESULTS The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. CONCLUSIONS AND IMPLICATIONS The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.
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Affiliation(s)
- Peng Xu
- School of Pharmacy, The Chinese University of Hong Kong, HKSAR, China
- Phase I Clinical Trial Center, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Raymond S M Wong
- Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaoyu Yan
- School of Pharmacy, The Chinese University of Hong Kong, HKSAR, China
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4
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Galy B, Conrad M, Muckenthaler M. Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol 2024; 25:133-155. [PMID: 37783783 DOI: 10.1038/s41580-023-00648-1] [Citation(s) in RCA: 249] [Impact Index Per Article: 249.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2023] [Indexed: 10/04/2023]
Abstract
In mammals, hundreds of proteins use iron in a multitude of cellular functions, including vital processes such as mitochondrial respiration, gene regulation and DNA synthesis or repair. Highly orchestrated regulatory systems control cellular and systemic iron fluxes ensuring sufficient iron delivery to target proteins is maintained, while limiting its potentially deleterious effects in iron-mediated oxidative cell damage and ferroptosis. In this Review, we discuss how cells acquire, traffick and export iron and how stored iron is mobilized for iron-sulfur cluster and haem biogenesis. Furthermore, we describe how these cellular processes are fine-tuned by the combination of various sensory and regulatory systems, such as the iron-regulatory protein (IRP)-iron-responsive element (IRE) network, the nuclear receptor co-activator 4 (NCOA4)-mediated ferritinophagy pathway, the prolyl hydroxylase domain (PHD)-hypoxia-inducible factor (HIF) axis or the nuclear factor erythroid 2-related factor 2 (NRF2) regulatory hub. We further describe how these pathways interact with systemic iron homeostasis control through the hepcidin-ferroportin axis to ensure appropriate iron fluxes. This knowledge is key for the identification of novel therapeutic opportunities to prevent diseases of cellular and/or systemic iron mismanagement.
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Affiliation(s)
- Bruno Galy
- German Cancer Research Center (DKFZ), Division of Virus-associated Carcinogenesis (F170), Heidelberg, Germany
| | - Marcus Conrad
- Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Martina Muckenthaler
- Department of Paediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Heidelberg, Germany.
- Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
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5
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Zamanian MY, Ivraghi MS, Gupta R, Prasad KDV, Alsaab HO, Hussien BM, Ahmed H, Ramadan MF, Golmohammadi M, Nikbakht N, Oz T, Kujawska M. miR-221 and Parkinson's disease: A biomarker with therapeutic potential. Eur J Neurosci 2024; 59:283-297. [PMID: 38043936 DOI: 10.1111/ejn.16207] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 12/05/2023]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein (α-syn) accumulation, mitochondrial dysfunction, oxidative stress and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation and apoptosis. miR-221 promotes neuronal survival against oxidative stress and neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of these studies, (1) miR-221 protects PC12 cells against oxidative stress induced by 6-hydroxydopamine; (2) miR-221 prevents Bax/caspase-3 signalling activation by stopping Bim; (3) miR-221 has moderate predictive power for PD; (4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; and (5) miRNA-221 controls cell viability and apoptosis by manipulating the Akt signalling pathway in PD. This review study suggested that miR-221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Physiology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Reena Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - K D V Prasad
- Symbiosis Institute of Business Management (SIBM), Hyderabad, India
- Symbiosis International (Deemed University) (SIU), Hyderabad, Telangana, India
| | - Hashem O Alsaab
- Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, Islamic University, Najaf, Iraq
| | - Hazem Ahmed
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikta Nikbakht
- Department of Physical Medicine and Rehabilitation, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Tuba Oz
- Department of Toxicology, Poznan University of Medical Sciences, Poznań, Poland
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Poznań, Poland
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6
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Brans V, Gray MD, Sezgin E, Stride EPJ. Protein-Decorated Microbubbles for Ultrasound-Mediated Cell Surface Manipulation. ACS APPLIED BIO MATERIALS 2023; 6:5746-5758. [PMID: 38048163 PMCID: PMC10731656 DOI: 10.1021/acsabm.3c00861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/14/2023] [Accepted: 11/20/2023] [Indexed: 12/06/2023]
Abstract
Delivering cargo to the cell membranes of specific cell types in the body is a major challenge for a range of treatments, including immunotherapy. This study investigates employing protein-decorated microbubbles (MBs) and ultrasound (US) to "tag" cellular membranes of interest with a specific protein. Phospholipid-coated MBs were produced and functionalized with a model protein using a metallochelating complex through an NTA(Ni) and histidine residue interaction. Successful "tagging" of the cellular membrane was observed using microscopy in adherent cells and was promoted by US exposure. Further modification of the MB surface to enable selective binding to target cells was then achieved by functionalizing the MBs with a targeting protein (transferrin) that specifically binds to a receptor on the target cell membrane. Attachment and subsequent transfer of material from MBs functionalized with transferrin to the target cells significantly increased, even in the absence of US. This work demonstrates the potential of these MBs as a platform for the noninvasive delivery of proteins to the surface of specific cell types.
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Affiliation(s)
- Veerle
A. Brans
- Department
of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DL, U.K.
| | - Michael D. Gray
- Department
of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DL, U.K.
| | - Erdinc Sezgin
- Science
for Life Laboratory, Department of Women’s and Children’s
Health, Karolinska Institutet, 17165 Solna, Sweden
| | - Eleanor P. J. Stride
- Department
of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DL, U.K.
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7
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Enns CA, Weiskopf T, Zhang RH, Wu J, Jue S, Kawaguchi M, Kataoka H, Zhang AS. Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism. J Biol Chem 2023; 299:105238. [PMID: 37690687 PMCID: PMC10551898 DOI: 10.1016/j.jbc.2023.105238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/07/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023] Open
Abstract
Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6-/- mice revealed that increases in dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct iron-deficiency anemia. Interestingly, the increased iron in Tmprss6-/- mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that a lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.
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Affiliation(s)
- Caroline A Enns
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Tyler Weiskopf
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Richard H Zhang
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Jeffrey Wu
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Shall Jue
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Makiko Kawaguchi
- Faculty of Medicine, Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
| | - Hiroaki Kataoka
- Faculty of Medicine, Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan
| | - An-Sheng Zhang
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA.
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8
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Ginzburg Y, An X, Rivella S, Goldfarb A. Normal and dysregulated crosstalk between iron metabolism and erythropoiesis. eLife 2023; 12:e90189. [PMID: 37578340 PMCID: PMC10425177 DOI: 10.7554/elife.90189] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023] Open
Abstract
Erythroblasts possess unique characteristics as they undergo differentiation from hematopoietic stem cells. During terminal erythropoiesis, these cells incorporate large amounts of iron in order to generate hemoglobin and ultimately undergo enucleation to become mature red blood cells, ultimately delivering oxygen in the circulation. Thus, erythropoiesis is a finely tuned, multifaceted process requiring numerous properly timed physiological events to maintain efficient production of 2 million red blood cells per second in steady state. Iron is required for normal functioning in all human cells, the erythropoietic compartment consuming the majority in light of the high iron requirements for hemoglobin synthesis. Recent evidence regarding the crosstalk between erythropoiesis and iron metabolism sheds light on the regulation of iron availability by erythroblasts and the consequences of insufficient as well as excess iron on erythroid lineage proliferation and differentiation. In addition, significant progress has been made in our understanding of dysregulated iron metabolism in various congenital and acquired malignant and non-malignant diseases. Finally, we report several actual as well as theoretical opportunities for translating the recently acquired robust mechanistic understanding of iron metabolism regulation to improve management of patients with disordered erythropoiesis, such as anemia of chronic inflammation, β-thalassemia, polycythemia vera, and myelodysplastic syndromes.
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Affiliation(s)
- Yelena Ginzburg
- Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Xiuli An
- LFKRI, New York Blood CenterNew YorkUnited States
| | - Stefano Rivella
- Department of Pediatrics, Division of Hematology, The Children’s Hospital of PhiladelphiaPhiladelphiaUnited States
- Cell and Molecular Biology affinity group (CAMB), University of PennsylvaniaPhiladelphiaUnited States
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics at the Children’s Hospital of PhiladelphiaPhiladelphiaUnited States
- Penn Center for Musculoskeletal Disorders at the Children’s Hospital of PhiladelphiaPhiladelphiaUnited States
- Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Institute for Regenerative Medicine at University of PennsylvaniaPhiladelphiaUnited States
- RNA Institute at University of PennsylvaniaPhiladelphiaUnited States
| | - Adam Goldfarb
- Department of Pathology, University of VirginiaCharlottesvilleUnited States
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9
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Ginzburg YZ. Hepcidin and its multiple partners: Complex regulation of iron metabolism in health and disease. VITAMINS AND HORMONES 2023; 123:249-284. [PMID: 37717987 DOI: 10.1016/bs.vh.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
The peptide hormone hepcidin is central to the regulation of iron metabolism, influencing the movement of iron into the circulation and determining total body iron stores. Its effect on a cellular level involves binding ferroportin, the main iron export protein, preventing iron egress and leading to iron sequestration within ferroportin-expressing cells. Hepcidin expression is enhanced by iron loading and inflammation and suppressed by erythropoietic stimulation. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis as occurs in anemia of chronic inflammation. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload such as hereditary hemochromatosis and iron loading anemias. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we assess the complex regulation of hepcidin, delineate the many binding partners involved in its regulation, and present an update on the development of hepcidin agonists and antagonists in various clinical scenarios.
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Affiliation(s)
- Yelena Z Ginzburg
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United Sates.
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10
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Handa S, Ginzburg Y, Hoffman R, Kremyanskaya M. Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis. Curr Opin Hematol 2023; 30:45-52. [PMID: 36728649 PMCID: PMC9908837 DOI: 10.1097/moh.0000000000000747] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE OF REVIEW Development of hepcidin therapeutics has been a ground-breaking discovery in restoring iron homeostasis in several haematological disorders. The hepcidin mimetic, rusfertide, is in late-stage clinical development for treating polycythemia vera patients with a global phase 3 trial [NCT05210790] currently underway. Rusfertide serves as the first possible noncytoreductive therapeutic option to maintain haematocrit control and avoid phlebotomy in polycythemia vera patients. In this comprehensive review, we discuss the pathobiology of dysregulated iron metabolism in polycythemia vera, provide the rationale for targeting the hepcidin-ferroportin axis and elaborate on the preclinical and clinical trial evidence supporting the role of hepcidin mimetics in polycythemia vera. RECENT FINDINGS Recently, updated results from two phase 2 clinical trials [NCT04057040 & NCT04767802] of rusfertide (PTG300) demonstrate that the drug is highly effective in eliminating the need for therapeutic phlebotomies, normalizing haematological parameters, repleting iron stores and relieving constitutional symptoms in patients with polycythemia vera. In light of these findings, additional hepcidin mimetic agents are also being evaluated in polycythemia vera patients. SUMMARY Hepcidin agonists essentially serve as a 'chemical phlebotomy' and are poised to vastly improve the quality of life for phlebotomy requiring polycythemia vera patients.
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Affiliation(s)
- Shivani Handa
- Tisch Cancer Institute, Division of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Yelena Ginzburg
- Tisch Cancer Institute, Division of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Ronald Hoffman
- Tisch Cancer Institute, Division of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Marina Kremyanskaya
- Tisch Cancer Institute, Division of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
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11
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Xiao X, Moschetta GA, Xu Y, Fisher AL, Alfaro-Magallanes VM, Dev S, Wang CY, Babitt JL. Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia. Blood 2023; 141:422-432. [PMID: 36322932 PMCID: PMC9936306 DOI: 10.1182/blood.2022017811] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia. Compared with Tfrcfl/fl;Alb-Cre- controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre- controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre- mice, ablation of hepatocyte Tfrc in a mouse model of β-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia.
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Affiliation(s)
- Xia Xiao
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Gillian A. Moschetta
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Yang Xu
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Allison L. Fisher
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | - Som Dev
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Chia-Yu Wang
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Jodie L. Babitt
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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12
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Di Modica SM, Tanzi E, Olivari V, Lidonnici MR, Pettinato M, Pagani A, Tiboni F, Furiosi V, Silvestri L, Ferrari G, Rivella S, Nai A. Transferrin receptor 2 (Tfr2) genetic deletion makes transfusion-independent a murine model of transfusion-dependent β-thalassemia. Am J Hematol 2022; 97:1324-1336. [PMID: 36071579 PMCID: PMC9540808 DOI: 10.1002/ajh.26673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 01/24/2023]
Abstract
β-thalassemia is a genetic disorder caused by mutations in the β-globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion-dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications. Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron-regulatory hormone hepcidin in the liver and a modulator of erythropoietin signaling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron-overload in non-TDT mice, both as a monotherapy and, even more strikingly, in combination with iron-restricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here, we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbbth1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α-globin, which partially corrects the unbalance with β-globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long-term blood transfusions required for survival of Hbbth1/th2 animals, preventing mortality due to chronic anemia and reducing transfusion-associated complications, such as progressive iron-loading. Altogether, TFR2 targeting might represent a promising therapeutic option also for TDT.
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Affiliation(s)
- Simona Maria Di Modica
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly
| | - Emanuele Tanzi
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly
| | - Violante Olivari
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly,Vita Salute San Raffaele UniversityMilanItaly
| | - Maria Rosa Lidonnici
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)Ospedale San RaffaeleMilanItaly
| | - Mariateresa Pettinato
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly,Vita Salute San Raffaele UniversityMilanItaly
| | - Alessia Pagani
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly
| | - Francesca Tiboni
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)Ospedale San RaffaeleMilanItaly
| | - Valeria Furiosi
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly
| | - Laura Silvestri
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly,Vita Salute San Raffaele UniversityMilanItaly
| | - Giuliana Ferrari
- Vita Salute San Raffaele UniversityMilanItaly,San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)Ospedale San RaffaeleMilanItaly
| | - Stefano Rivella
- Division of Hematology, Department of PediatricsChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Antonella Nai
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell BiologyOspedale San RaffaeleMilanItaly,Vita Salute San Raffaele UniversityMilanItaly
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13
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Li D, Pi W, Sun Z, Liu X, Jiang J. Ferroptosis and its role in cardiomyopathy. Biomed Pharmacother 2022; 153:113279. [PMID: 35738177 DOI: 10.1016/j.biopha.2022.113279] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 12/09/2022] Open
Abstract
Heart disease is the leading cause of death worldwide. Cardiomyopathy is a disease characterized by the heart muscle damage, resulting heart in a structurally and functionally change, as well as heart failure and sudden cardiac death. The key pathogenic factor of cardiomyopathy is the loss of cardiomyocytes, but the related molecular mechanisms remain unclear. Ferroptosis is a newly discovered regulated form of cell death, characterized by iron accumulation and lipid peroxidation during cell death. Recent studies have shown that ferroptosis plays an important regulatory roles in the occurrence and development of many heart diseases such as myocardial ischemia/reperfusion injury, cardiomyopathy and heart failure. However, the systemic association of ferroptosis and cardiomyopathy remains largely unknown and needs to be elucidated. In this review, we provide an overview of the molecular mechanisms of ferroptosis and its role in individual cardiomyopathies, highlight that targeting ferroptosis maybe a potential therapeutic strategy for cardiomyopathy therapy in the future.
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Affiliation(s)
- Danlei Li
- Department of Cardiology, Taizhou Hospital of Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Wenhu Pi
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Affiliated Taizhou hospital of Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Zhenzhu Sun
- Department of Cardiology, Taizhou Hospital of Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Xiaoman Liu
- Department of Cardiology, Taizhou Hospital of Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Jianjun Jiang
- Department of Cardiology, Taizhou Hospital of Wenzhou Medical University, Linhai 317000, Zhejiang Province, China.
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Enns CA, Jue S, Zhang AS. Hepatocyte neogenin is required for hemojuvelin-mediated hepcidin expression and iron homeostasis in mice. Blood 2021; 138:486-499. [PMID: 33824974 PMCID: PMC8370464 DOI: 10.1182/blood.2020009485] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/26/2021] [Indexed: 12/21/2022] Open
Abstract
Neogenin (NEO1) is a ubiquitously expressed multifunctional transmembrane protein. It interacts with hemojuvelin (HJV), a BMP coreceptor that plays a pivotal role in hepatic hepcidin expression. Earlier studies suggest that the function of HJV relies on its interaction with NEO1. However, the role of NEO1 in iron homeostasis remains controversial because of the lack of an appropriate animal model. Here, we generated a hepatocyte-specific Neo1 knockout (Neo1fl/fl;Alb-Cre+) mouse model that circumvented the developmental and lethality issues of the global Neo1 mutant. Results show that ablation of hepatocyte Neo1 decreased hepcidin expression and caused iron overload. This iron overload did not result from altered iron utilization by erythropoiesis. Replacement studies revealed that expression of the Neo1L1046E mutant that does not interact with Hjv, was unable to correct the decreased hepcidin expression and high serum iron in Neo1fl/fl;Alb-Cre+ mice. In Hjv-/- mice, expression of HjvA183R mutant that has reduced interaction with Neo1, also displayed a blunted induction of hepcidin expression. These observations indicate that Neo1-Hjv interaction is essential for hepcidin expression. Further analyses suggest that the Hjv binding triggered the cleavage of the Neo1 cytoplasmic domain by a protease, which resulted in accumulation of truncated Neo1 on the plasma membrane. Additional studies did not support that Neo1 functions by inhibiting Hjv shedding as previously proposed. Together, our data favor a model in which Neo1 interaction with Hjv leads to accumulation of cleaved Neo1 on the plasma membrane, where Neo1 acts as a scaffold to induce the Bmp signaling and hepcidin expression.
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Affiliation(s)
- Caroline A Enns
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR
| | - Shall Jue
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR
| | - An-Sheng Zhang
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR
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15
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Tackling the unknowns in understanding and management of hospital acquired anemia. Blood Rev 2021; 49:100830. [PMID: 33810899 DOI: 10.1016/j.blre.2021.100830] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/21/2021] [Accepted: 03/21/2021] [Indexed: 01/29/2023]
Abstract
Hospital acquired anemia (HAA) has been a recognized entity for nearly 50 years. Despite multiple hypotheses, a mechanistic understanding is lacking, and targeted interventions have not yet yielded significantly impactful results. Known risk factors include advanced age, multiple co-morbidities, low bone marrow reserve, admission to the intensive care unit, and frequent phlebotomy. However, confounding variables in many studies continues to complicate the identification of additional risk factors. Improved understanding of iron metabolism, erythropoiesis, and the erythroid iron restriction response in the last few decades, as well as the recent demonstration of poor outcomes correlating with increased transfusion have refocused attention on HAA. While retrospective database studies provide ample correlative data between 1) HAA and poor outcomes; 2) reduction of phlebotomy volume and decrease in transfusion requirement; and 3) over-transfusion and increased mortality, no causal link between reduced phlebotomy volume, decreased rates of HAA, and improved mortality or other relevant outcomes have been definitely established. Here, we review the current state of knowledge and provide a summary of potential directions to understand and mitigate HAA. There are at present no clear guidelines on whether and when to evaluate hospitalized patients for underlying causes of anemia. We thus provide a guide for clinicians in general practice toward identifying patients at the highest risk for HAA, decreasing blood loss through phlebotomy to the greatest degree feasible, and evaluating and treating reversible causes of anemia in a targeted population.
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16
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Urrutia PJ, Bórquez DA, Núñez MT. Inflaming the Brain with Iron. Antioxidants (Basel) 2021; 10:antiox10010061. [PMID: 33419006 PMCID: PMC7825317 DOI: 10.3390/antiox10010061] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 02/06/2023] Open
Abstract
Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood-brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD.
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Affiliation(s)
- Pamela J. Urrutia
- Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile;
| | - Daniel A. Bórquez
- Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, 8370007 Santiago, Chile;
| | - Marco Tulio Núñez
- Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile;
- Correspondence: ; Tel.: +56-2-29787360
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17
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Inoue H, Hanawa N, Katsumata SI, Aizawa Y, Katsumata-Tsuboi R, Tanaka M, Takahashi N, Uehara M. Iron deficiency negatively regulates protein methylation via the downregulation of protein arginine methyltransferase. Heliyon 2020; 6:e05059. [PMID: 33033759 PMCID: PMC7533365 DOI: 10.1016/j.heliyon.2020.e05059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/25/2020] [Accepted: 09/21/2020] [Indexed: 12/21/2022] Open
Abstract
Iron is an essential trace metal for all biological processes and plays a role in almost every aspect of body growth. Previously, we found that iron-depletion downregulated the expression of proteins, arginine methyltransferase-1 and 3 (PRMT1 and PRMT3), by an iron-specific chelator, deferoxamine (DFO), in rat liver FAO cell line using DNA microarray analysis (unpublished data). However, regulatory mechanisms underlying the association between iron deficiency and PRMT expression are unclear in vitro and in vivo. In the present study, we revealed that the treatment of cells with two iron-specific chelators, DFO and deferasirox (DFX), downregulated the gene and protein expression of PRMT1 and 3 as compared with the untreated cells. Subsequently, DFO and DFX treatments decreased protein methylation. Importantly, these effects were attenuated by a holo-transferrin treatment. Furthermore, weanling Wistar-strain rats were fed a control diet or an iron-deficient diet for 4 weeks. Dietary iron deficiency was found to decrease the concentration of hemoglobin and liver iron while increasing the heart weight. PRMT and protein methylation levels were also significantly reduced in the iron-deficient group as compared to the control group. To our knowledge, this is the first study to demonstrate that PRMT levels and protein methylation are reduced in iron-deficient models, in vitro and in vivo.
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Affiliation(s)
- Hirofumi Inoue
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
| | - Nobuaki Hanawa
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
| | - Shin-Ichi Katsumata
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
| | - Yumi Aizawa
- Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Tokyo, Japan
| | - Rie Katsumata-Tsuboi
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
| | - Miori Tanaka
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
| | - Nobuyuki Takahashi
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
| | - Mariko Uehara
- Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Japan
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18
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Xiao X, Alfaro-Magallanes VM, Babitt JL. Bone morphogenic proteins in iron homeostasis. Bone 2020; 138:115495. [PMID: 32585319 PMCID: PMC7453787 DOI: 10.1016/j.bone.2020.115495] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/12/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023]
Abstract
The bone morphogenetic protein (BMP)-SMAD signaling pathway plays a central role in regulating hepcidin, which is the master hormone governing systemic iron homeostasis. Hepcidin is produced by the liver and acts on the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores, thereby providing adequate iron for red blood cell production, while limiting the toxic effects of excess iron. BMP6 and BMP2 ligands produced by liver endothelial cells bind to BMP receptors and the coreceptor hemojuvelin (HJV) on hepatocytes to activate SMAD1/5/8 signaling, which directly upregulates hepcidin transcription. Most major signals that influence hepcidin production, including iron, erythropoietic drive, and inflammation, intersect with the BMP-SMAD pathway to regulate hepcidin transcription. Mutation or inactivation of BMP ligands, BMP receptors, HJV, SMADs or other proteins that modulate the BMP-SMAD pathway result in hepcidin dysregulation, leading to iron-related disorders, such as hemochromatosis and iron refractory iron deficiency anemia. Pharmacologic modulators of the BMP-SMAD pathway have shown efficacy in pre-clinical models to regulate hepcidin expression and treat iron-related disorders. This review will discuss recent insights into the role of the BMP-SMAD pathway in regulating hepcidin to control systemic iron homeostasis.
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Affiliation(s)
- Xia Xiao
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Víctor M Alfaro-Magallanes
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; LFE Research Group, Department of Health and Human Performance, Faculty of Physical Activity and Sport Sciences, Universidad Politécnica de Madrid (UPM), Madrid, Spain
| | - Jodie L Babitt
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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19
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Ścibior A, Hus I, Mańko J, Jawniak D. Evaluation of the level of selected iron-related proteins/receptors in the liver of rats during separate/combined vanadium and magnesium administration. J Trace Elem Med Biol 2020; 61:126550. [PMID: 32464446 DOI: 10.1016/j.jtemb.2020.126550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 04/17/2020] [Accepted: 05/08/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND The current knowledge about the effects of vanadium (V) on iron (Fe)-related proteins and Fe homeostasis (which is regulated at the systemic, organelle, and cellular levels) is still insufficient. OBJECTIVE This fact and our earlier results prompted us to conduct studies with the aim to explain the mechanism of anemia accompanied by a rise in hepatic and splenic Fe deposition in rats receiving sodium metavanadate (SMV) separately and in combination with magnesium sulfate (MS). RESULTS We demonstrated for the first time that SMV (0.125 mg V/mL) administered to rats individually and in conjunction with MS (0.06 mg Mg/mL) for 12 weeks did not cause significant differences in the hepatic hepcidin (Hepc) and hemojuvelin (HJV) concentrations, compared to the control. In comparison with the control, there were no significant changes in the concentration of transferrin receptor 1 (TfR1) in the liver of rats treated with SMV and MS alone (in both cases only a downward trend of 14% and 15% was observed). However, a significant reduction in the hepatic TfR1 level was found in rats receiving SMV and MS simultaneously. In turn, the concentration of transferrin receptor 2 (TfR2) showed an increasing trend in the liver of rats treated with SMV and/or MS. CONCLUSIONS The experimental data suggest that the pathomechanism of the SMV-induced anemia is not associated with the effect of V on the concentration of Hepc in the liver, as confirmed by the unaltered hepatic HJV and TfR1 levels. Therefore, further studies are needed in order to check whether anemia that developed in the rats at the SMV administration (a) results from the inhibitory effect of V on erythropoietin (EPO) production, (b) is related to the effect of V on the induction of matriptase-2 (TMPRSS6) expression, or (c) is associated with the influence of this metal on haem synthesis.
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Affiliation(s)
- Agnieszka Ścibior
- Laboratory of Oxidative Stress, Centre for Interdisciplinary Research, The John Paul II Catholic University of Lublin, Poland.
| | - Iwona Hus
- Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
| | - Joanna Mańko
- Clinic of Haematooncology and Bone Marrow Transplantation, Medical University, Lublin, Poland.
| | - Dariusz Jawniak
- Clinic of Haematooncology and Bone Marrow Transplantation, Medical University, Lublin, Poland.
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Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice. Blood 2020; 134:1547-1557. [PMID: 31439541 DOI: 10.1182/blood.2019002039] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 08/09/2019] [Indexed: 12/13/2022] Open
Abstract
The mechanisms underlying thrombocytosis in patients with iron deficiency anemia remain unknown. Here, we present findings that support the hypothesis that low iron biases the commitment of megakaryocytic (Mk)-erythroid progenitors (MEPs) toward the Mk lineage in both human and mouse. In MEPs of transmembrane serine protease 6 knockout (Tmprss6-/-) mice, which exhibit iron deficiency anemia and thrombocytosis, we observed a Mk bias, decreased labile iron, and decreased proliferation relative to wild-type (WT) MEPs. Bone marrow transplantation assays suggest that systemic iron deficiency, rather than a local role for Tmprss6-/- in hematopoietic cells, contributes to the MEP lineage commitment bias observed in Tmprss6-/- mice. Nontransgenic mice with acquired iron deficiency anemia also show thrombocytosis and Mk-biased MEPs. Gene expression analysis reveals that messenger RNAs encoding genes involved in metabolic, vascular endothelial growth factor, and extracellular signal-regulated kinase (ERK) pathways are enriched in Tmprss6-/- vs WT MEPs. Corroborating our findings from the murine models of iron deficiency anemia, primary human MEPs exhibit decreased proliferation and Mk-biased commitment after knockdown of transferrin receptor 2, a putative iron sensor. Signal transduction analyses reveal that both human and murine MEP have lower levels of phospho-ERK1/2 in iron-deficient conditions compared with controls. These data are consistent with a model in which low iron in the marrow environment affects MEP metabolism, attenuates ERK signaling, slows proliferation, and biases MEPs toward Mk lineage commitment.
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21
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Sun P, Wang S, Wang J, Sun J, Peng M, Shi P. The involvement of iron in chemerin induced cell cycle arrest in human hepatic carcinoma SMMC7721 cells. Metallomics 2019; 10:838-845. [PMID: 29872820 DOI: 10.1039/c8mt00099a] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chemerin exhibits a tumor-inhibitory role in hepatocellular carcinoma. However, the effect of chemerin on essential metal elements in hepatic cells remains unclear. In our study, the contents of six important metal ions, including potassium, calcium, sodium, magnesium, iron and zinc, were detected in human hepatoma SMMC7721 and immortal hepatic QSG7701 cells by ICP-AES. The data showed that chemerin only decreases the content of intracellular iron in SMMC7721 cells. The reduction was due to the blockage of iron entry through the decrease in the mRNA levels of divalent metal transporter 1, iron regulatory proteins and transferrin receptors. Furthermore, the reduction of the cellular iron content induced alterations of p53-p27-p21 signaling to arrest the cell cycle at S phase in SMMC7721 cells treated by chemerin. Conversely, iron addition led to recovery from the inhibitory effect of chemerin on SMMC7721 cells. The results suggest that chemerin plays an important role in inhibiting the cell proliferation of hepatocellular carcinomas by interfering with cellular iron homeostasis in this type of tumors.
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Affiliation(s)
- Pengcheng Sun
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
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22
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Frýdlová J, Rogalsky DW, Truksa J, Nečas E, Vokurka M, Krijt J. Effect of stimulated erythropoiesis on liver SMAD signaling pathway in iron-overloaded and iron-deficient mice. PLoS One 2019; 14:e0215028. [PMID: 30958854 PMCID: PMC6453526 DOI: 10.1371/journal.pone.0215028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 03/25/2019] [Indexed: 12/21/2022] Open
Abstract
Expression of hepcidin, the hormone regulating iron homeostasis, is increased by iron overload and decreased by accelerated erythropoiesis or iron deficiency. The purpose of the study was to examine the effect of these stimuli, either alone or in combination, on the main signaling pathway controlling hepcidin biosynthesis in the liver, and on the expression of splenic modulators of hepcidin biosynthesis. Liver phosphorylated SMAD 1 and 5 proteins were determined by immunoblotting in male mice treated with iron dextran, kept on an iron deficient diet, or administered recombinant erythropoietin for four consecutive days. Administration of iron increased liver phosphorylated SMAD protein content and hepcidin mRNA content; subsequent administration of erythropoietin significantly decreased both the iron-induced phosphorylated SMAD proteins and hepcidin mRNA. These results are in agreement with the recent observation that erythroferrone binds and inactivates the BMP6 protein. Administration of erythropoietin substantially increased the amount of erythroferrone and transferrin receptor 2 proteins in the spleen; pretreatment with iron did not influence the erythropoietin-induced content of these proteins. Erythropoietin-treated iron-deficient mice displayed smaller spleen size in comparison with erythropoietin-treated mice kept on a control diet. While the erythropoietin-induced increase in splenic erythroferrone protein content was not significantly affected by iron deficiency, the content of transferrin receptor 2 protein was lower in the spleens of erythropoietin-treated mice kept on iron-deficient diet, suggesting posttranscriptional regulation of transferrin receptor 2. Interestingly, iron deficiency and erythropoietin administration had additive effect on hepcidin gene downregulation in the liver. In mice subjected both to iron deficiency and erythropoietin administration, the decrease of hepcidin expression was much more pronounced than the decrease in phosphorylated SMAD protein content or the decrease in the expression of the SMAD target genes Id1 and Smad7. These results suggest the existence of another, SMAD-independent pathway of hepcidin gene downregulation.
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Affiliation(s)
- Jana Frýdlová
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Daniel W. Rogalsky
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jaroslav Truksa
- Laboratory of Tumour Resistance, Institute of Biotechnology, BIOCEV Research Center, Czech Academy of Sciences, Vestec, Czech Republic
| | - Emanuel Nečas
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Martin Vokurka
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Krijt
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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23
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Kawabata H. Transferrin and transferrin receptors update. Free Radic Biol Med 2019; 133:46-54. [PMID: 29969719 DOI: 10.1016/j.freeradbiomed.2018.06.037] [Citation(s) in RCA: 414] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 06/29/2018] [Accepted: 06/29/2018] [Indexed: 12/20/2022]
Abstract
In vertebrates, transferrin (Tf) safely delivers iron through circulation to cells. Tf-bound iron is incorporated through Tf receptor (TfR) 1-mediated endocytosis. TfR1 can mediate cellular uptake of both Tf and H-ferritin, an iron storage protein. New World arenaviruses, which cause hemorrhagic fever, and Plasmodium vivax use TfR1 for entry into host cells. Human TfR2, another receptor for Tf, is predominantly expressed in hepatocytes and erythroid precursors, and holo-Tf dramatically upregulates its expression. TfR2 forms a complex with hemochromatosis protein, HFE, and serves as a component of the iron sensing machinery in hepatocytes. Defects in TfR2 cause systemic iron overload, hemochromatosis, through down-regulation of hepcidin. In erythroid cells, TfR2 forms a complex with the erythropoietin receptor and regulates erythropoiesis. TfR2 facilitates iron transport from lysosomes to mitochondria in erythroblasts and dopaminergic neurons. Administration of apo-Tf, which scavenges free iron, has been explored for various clinical conditions including atransferrinemia, iron overload, and tissue ischemia. Apo-Tf has also been shown to ameliorate anemia in animal models of β-thalassemia. In this review, I provide an update and summary on our knowledge of mammalian Tf and its receptors.
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Affiliation(s)
- Hiroshi Kawabata
- Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa-ken 920-0293, Japan.
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Abstract
Hepcidin is central to regulation of iron metabolism. Its effect on a cellular level involves binding ferroportin, the main iron export protein, resulting in its internalization and degradation and leading to iron sequestration within ferroportin-expressing cells. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we present an overview of and rationale for exploring the development of hepcidin agonists and antagonists in various clinical scenarios.
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Affiliation(s)
- Yelena Z Ginzburg
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load. Blood 2018; 133:344-355. [PMID: 30538134 DOI: 10.1182/blood-2018-05-850404] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 12/04/2018] [Indexed: 02/06/2023] Open
Abstract
Transferrin receptor 1 (Tfr1) mediates uptake of circulating transferrin-bound iron to developing erythroid cells and other cell types. Its critical physiological function is highlighted by the embryonic lethal phenotype of Tfr1-knockout (Tfrc-/-) mice and the pathologies of several tissue-specific knockouts. We generated TfrcAlb-Cre mice bearing hepatocyte-specific ablation of Tfr1 to explore implications in hepatocellular and systemic iron homeostasis. TfrcAlb-Cre mice are viable and do not display any apparent liver pathology. Nevertheless, their liver iron content (LIC) is lower compared with that of control Tfrcfl/fl littermates as a result of the reduced capacity of Tfr1-deficient hepatocytes to internalize iron from transferrin. Even though liver Hamp messenger RNA (mRNA) and serum hepcidin levels do not differ between TfrcAlb-Cre and Tfrcfl/fl mice, Hamp/LIC and hepcidin/LIC ratios are significantly higher in the former. Importantly, this is accompanied by modest hypoferremia and microcytosis, and it predisposes TfrcAlb-Cre mice to iron-deficiency anemia. TfrcAlb-Cre mice appropriately regulate Hamp expression following dietary iron manipulations or holo-transferrin injection. Holo-transferrin also triggers proper induction of Hamp mRNA, ferritin, and Tfr2 in primary TfrcAlb-Cre hepatocytes. We further show that these cells can acquire 59Fe from 59Fe-transferrin, presumably via Tfr2. We conclude that Tfr1 is redundant for basal hepatocellular iron supply but essential for fine-tuning hepcidin responses according to the iron load of hepatocytes. Our data are consistent with an inhibitory function of Tfr1 on iron signaling to hepcidin via its interaction with Hfe. Moreover, they highlight hepatocellular Tfr1 as a link between cellular and systemic iron-regulatory pathways.
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Abstract
The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.
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Frýdlová J, Rogalsky DW, Truksa J, Traeger L, Steinbicker AU, Vokurka M, Krijt J. Liver HFE protein content is posttranscriptionally decreased in iron-deficient mice and rats. Am J Physiol Gastrointest Liver Physiol 2018; 315:G560-G568. [PMID: 29927322 DOI: 10.1152/ajpgi.00070.2018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although the relationship between hereditary hemochromatosis and mutations in the HFE gene was discovered more than 20 years ago, information on the in vivo regulation of HFE protein expression is still limited. The purpose of the study was to determine the response of liver HFE protein content to iron deficiency in mice and rats by immunoblotting. Attempts to visualize the HFE protein in whole liver homogenates were unsuccessful; however, HFE could be detected in liver microsomes or in plasma membrane-enriched fractions. Five-week-old male C57BL/6 mice fed an iron-deficient diet for 4 wk presented with a significant decrease in liver iron content and liver Hamp expression, as well as with a significant decrease in liver HFE protein content. Rats fed an iron-deficient diet for 4 wk also displayed significant decrease in liver Hamp expression and liver HFE protein content. These results suggest that the downregulation of HFE-dependent signaling may contribute to decreased Hamp gene expression in states of prolonged iron deficiency. It has recently been proposed that HFE protein could be a potential target of matriptase-2, a hepatocyte protease mutated in iron-refractory iron deficiency anemia. However, immunoblot analysis of HFE protein in the livers from Tmprss6-mutated mask mice did not show evidence of matriptase-2-dependent HFE protein cleavage. In addition, no indication of HFE protein cleavage was seen in iron-deficient rats, whereas the full-length matriptase-2 protein content in the same animals was significantly increased. These results suggest that HFE is probably not a major physiological target of matriptase-2. NEW & NOTEWORTHY Feeding of iron-deficient diet for 4 wk decreased liver HFE protein content in both mice and rats, suggesting that decreased HFE-dependent signaling may contribute to hepcidin downregulation in iron deficiency. There was no difference in HFE protein band appearance between matriptase-2-mutated mask mice and wild-type mice, indicating that HFE is probably not a major physiological substrate of matriptase-2-mediated protease activity in vivo.
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Affiliation(s)
- Jana Frýdlová
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University , Prague , Czech Republic
| | - Daniel W Rogalsky
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University , Prague , Czech Republic
| | - Jaroslav Truksa
- Laboratory of Tumour Resistance, Institute of Biotechnology, Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec Research Center, Czech Academy of Sciences, Vestec, Czech Republic
| | - Lisa Traeger
- Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Muenster, Muenster University , Muenster , Germany
| | - Andrea U Steinbicker
- Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Muenster, Muenster University , Muenster , Germany
| | - Martin Vokurka
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University , Prague , Czech Republic
| | - Jan Krijt
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University , Prague , Czech Republic
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Mirciov CSG, Wilkins SJ, Hung GCC, Helman SL, Anderson GJ, Frazer DM. Circulating iron levels influence the regulation of hepcidin following stimulated erythropoiesis. Haematologica 2018; 103:1616-1626. [PMID: 29903760 PMCID: PMC6165793 DOI: 10.3324/haematol.2017.187245] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 06/11/2018] [Indexed: 01/01/2023] Open
Abstract
The stimulation of erythrocyte formation increases the demand for iron by the bone marrow and this in turn may affect the levels of circulating diferric transferrin. As this molecule influences the production of the iron regulatory hormone hepcidin, we hypothesized that erythropoiesis-driven changes in diferric transferrin levels could contribute to the decrease in hepcidin observed following the administration of erythropoietin. To examine this, we treated mice with erythropoietin and examined diferric transferrin at various time points up to 18 hours. We also investigated the effect of altering diferric transferrin levels on erythropoietin-induced inhibition of Hamp1, the gene encoding hepcidin. We detected a decrease in diferric transferrin levels 5 hours after erythropoietin injection and prior to any inhibition of the hepatic Hamp1 message. Diferric transferrin returned to control levels 12 hours after erythropoietin injection and had increased beyond control levels by 18 hours. Increasing diferric transferrin levels via intravenous iron injection prevented the inhibition of Hamp1 expression by erythropoietin without altering hepatic iron concentration or the expression of Erfe, the gene encoding erythroferrone. These results suggest that diferric transferrin likely contributes to the inhibition of hepcidin production in the period shortly after injection of erythropoietin and that, under the conditions examined, increasing diferric transferrin levels can overcome the inhibitory effect of erythroferrone on hepcidin production. They also imply that the decrease in Hamp1 expression in response to an erythropoietic stimulus is likely to be mediated by multiple signals.
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Affiliation(s)
- Cornel S G Mirciov
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Medicine, The University of Queensland, St Lucia, Australia
| | - Sarah J Wilkins
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Grace C C Hung
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Sheridan L Helman
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Biomedical Sciences, Queensland University of Technology, Gardens Point, Australia
| | - Gregory J Anderson
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Medicine, The University of Queensland, St Lucia, Australia.,School of Chemistry and Molecular Bioscience, The University of Queensland, St Lucia, Australia
| | - David M Frazer
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia .,School of Medicine, The University of Queensland, St Lucia, Australia
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Wessling-Resnick M. Crossing the Iron Gate: Why and How Transferrin Receptors Mediate Viral Entry. Annu Rev Nutr 2018; 38:431-458. [PMID: 29852086 DOI: 10.1146/annurev-nutr-082117-051749] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Because both the host and pathogen require iron, the innate immune response carefully orchestrates control over iron metabolism to limit its availability during times of infection. Nutritional iron deficiency can impair host immunity, while iron overload can cause oxidative stress to propagate harmful viral mutations. An emerging enigma is that many viruses use the primary gatekeeper of iron metabolism, the transferrin receptor, as a means to enter cells. Why and how this iron gate is a viral target for infection are the focus of this review.
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Affiliation(s)
- Marianne Wessling-Resnick
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA;
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30
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Affiliation(s)
- Jin Kyung Suh
- Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea
| | - In-sang Jeon
- Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea
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31
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Kleven MD, Jue S, Enns CA. Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms. Biochemistry 2018; 57:1552-1559. [PMID: 29388418 DOI: 10.1021/acs.biochem.8b00006] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hereditary hemochromatosis (HH), a disease marked by chronic iron overload from insufficient expression of the hormone hepcidin, is one of the most common genetic diseases. One form of HH (type III) results from mutations in transferrin receptor-2 (TfR2). TfR2 is postulated to be a part of signaling system that is capable of modulating hepcidin expression. However, the molecular details of TfR2's role in this system remain unclear. TfR2 is predicted to bind the iron carrier transferrin (Tf) when the iron saturation of Tf is high. To better understand the nature of these TfR-Tf interactions, a binding study with the full-length receptors was conducted. In agreement with previous studies with truncated forms of these receptors, holo-Tf binds to the TfR1 homologue significantly stronger than to TfR2. However, the binding constant for Tf-TfR2 is still far above that of physiological holo-Tf levels, inconsistent with the hypothetical model, suggesting that other factors mediate the interaction. One possible factor, apo-Tf, only weakly binds TfR2 at serum pH and thus will not be able to effectively compete with holo-Tf. Tf binding to a TfR2 chimera containing the TfR1 helical domain indicates that the differences in the helical domain account for differences in the on rate of Tf, and nonconserved inter-receptor interactions are necessary for the stabilization of the complex. Conserved residues at one possible site of stabilization, the apical arm junction, are not important for TfR1-Tf binding but are critical for the TfR2-Tf interaction. Our results highlight the differences in Tf interactions with the two TfRs.
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Affiliation(s)
- Mark D Kleven
- Department of Cell, Cancer and Developmental Biology , Oregon Health & Science University , 3181 SW Sam Jackson Park Road , Portland , Oregon 97201 , United States
| | - Shall Jue
- Department of Cell, Cancer and Developmental Biology , Oregon Health & Science University , 3181 SW Sam Jackson Park Road , Portland , Oregon 97201 , United States
| | - Caroline A Enns
- Department of Cell, Cancer and Developmental Biology , Oregon Health & Science University , 3181 SW Sam Jackson Park Road , Portland , Oregon 97201 , United States
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33
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Frýdlová J, Rychtarčíková Z, Gurieva I, Vokurka M, Truksa J, Krijt J. Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice. PLoS One 2017; 12:e0186844. [PMID: 29073189 PMCID: PMC5658091 DOI: 10.1371/journal.pone.0186844] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 10/09/2017] [Indexed: 11/30/2022] Open
Abstract
Tmprss6-mutated mask mice display iron deficiency anemia and high expression of hepcidin. The aim of the study was to determine the effect of erythropoietin administration on proteins participating in the control of iron homeostasis in the liver and spleen in C57BL/6 and mask mice. Administration of erythropoietin for four days at 50 IU/mouse/day increased hemoglobin and hematocrit in C57BL/6 mice, no such increase was seen in mask mice. Erythropoietin administration decreased hepcidin expression in C57BL/6 mice, but not in mask mice. Erythropoietin treatment significantly increased the spleen size in both C57BL/6 and mask mice. Furthermore, erythropoietin administration increased splenic Fam132b, Fam132a and Tfr2 mRNA content. At the protein level, erythropoietin increased the amount of splenic erythroferrone and transferrin receptor 2 both in C57BL/6 and mask mice. Splenic ferroportin content was decreased in erythropoietin-treated mask mice in comparison with erythropoietin-treated C57BL/6 mice. In mask mice, the amount of liver hemojuvelin was decreased in comparison with C57BL/6 mice. The pattern of hemojuvelin cleavage was different between C57BL/6 and mask mice: In both groups, a main hemojuvelin band was detected at approximately 52 kDa; in C57BL/6 mice, a minor cleaved band was seen at 47 kDa. In mask mice, the 47 kDa band was absent, but additional minor bands were detected at approximately 45 kDa and 48 kDa. The results provide support for the interaction between TMPRSS6 and hemojuvelin in vivo; they also suggest that hemojuvelin could be cleaved by another as yet unknown protease in the absence of functional TMPRSS6. The lack of effect of erythropoietin on hepcidin expression in mask mice can not be explained by changes in erythroferrone synthesis, as splenic erythroferrone content increased after erythropoietin administration in both C57BL/6 and mask mice.
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Affiliation(s)
- Jana Frýdlová
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Zuzana Rychtarčíková
- Laboratory of Tumour Resistance, Institute of Biotechnology, BIOCEV Research Center, Czech Academy of Sciences, Vestec, Czech Republic
- Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Iuliia Gurieva
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Martin Vokurka
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jaroslav Truksa
- Laboratory of Tumour Resistance, Institute of Biotechnology, BIOCEV Research Center, Czech Academy of Sciences, Vestec, Czech Republic
- * E-mail: (JT); (JK)
| | - Jan Krijt
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
- * E-mail: (JT); (JK)
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34
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Wahedi M, Wortham AM, Kleven MD, Zhao N, Jue S, Enns CA, Zhang AS. Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. J Biol Chem 2017; 292:18354-18371. [PMID: 28924039 DOI: 10.1074/jbc.m117.801795] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
Systemic iron homeostasis is maintained by regulation of iron absorption in the duodenum, iron recycling from erythrocytes, and iron mobilization from the liver and is controlled by the hepatic hormone hepcidin. Hepcidin expression is induced via the bone morphogenetic protein (BMP) signaling pathway that preferentially uses two type I (ALK2 and ALK3) and two type II (ActRIIA and BMPR2) BMP receptors. Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate this process presumably by forming a plasma membrane complex with BMP receptors. Matriptase-2 (MT2) is a protease and key suppressor of hepatic hepcidin expression and cleaves HJV. Previous studies have therefore suggested that MT2 exerts its inhibitory effect by inactivating HJV. Here, we report that MT2 suppresses hepcidin expression independently of HJV. In Hjv-/- mice, increased expression of exogenous MT2 in the liver significantly reduced hepcidin expression similarly as observed in wild-type mice. Exogenous MT2 could fully correct abnormally high hepcidin expression and iron deficiency in MT2-/- mice. In contrast to MT2, increased Hjv expression caused no significant changes in wild-type mice, suggesting that Hjv is not a limiting factor for hepcidin expression. Further studies revealed that MT2 cleaves ALK2, ALK3, ActRIIA, Bmpr2, Hfe, and, to a lesser extent, Hjv and Tfr2. MT2-mediated Tfr2 cleavage was also observed in HepG2 cells endogenously expressing MT2 and TfR2. Moreover, iron-loaded transferrin blocked MT2-mediated Tfr2 cleavage, providing further insights into the mechanism of Tfr2's regulation by transferrin. Together, these observations indicate that MT2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway.
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Affiliation(s)
- Mastura Wahedi
- From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 and
| | - Aaron M Wortham
- From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 and
| | - Mark D Kleven
- From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 and
| | - Ningning Zhao
- the Department of Nutritional Sciences, University of Arizona, Tucson, Arizona 85721
| | - Shall Jue
- From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 and
| | - Caroline A Enns
- From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 and
| | - An-Sheng Zhang
- From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 and
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35
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α7 nicotinic acetylcholine receptor signaling modulates the inflammatory phenotype of fetal brain microglia: first evidence of interference by iron homeostasis. Sci Rep 2017; 7:10645. [PMID: 28878260 PMCID: PMC5587535 DOI: 10.1038/s41598-017-09439-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 07/26/2017] [Indexed: 12/17/2022] Open
Abstract
Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of α7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective α7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, antagonistic α7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated α7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of α7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and α7nAChR signaling in neurodevelopment.
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36
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Papanikolaou G, Pantopoulos K. Systemic iron homeostasis and erythropoiesis. IUBMB Life 2017; 69:399-413. [DOI: 10.1002/iub.1629] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 03/16/2017] [Indexed: 01/01/2023]
Affiliation(s)
- George Papanikolaou
- Department of Nutrition and DieteticsSchool of Health Science and Education, Harokopion UniversityAthens Greece
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research and Department of MedicineMcGill UniversityMontreal Quebec Canada
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Rishi G, Secondes ES, Wallace DF, Subramaniam VN. Normal systemic iron homeostasis in mice with macrophage-specific deletion of transferrin receptor 2. Am J Physiol Gastrointest Liver Physiol 2016; 310:G171-80. [PMID: 26608187 DOI: 10.1152/ajpgi.00291.2015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/23/2015] [Indexed: 01/31/2023]
Abstract
Iron is an essential element, since it is a component of many macromolecules involved in diverse physiological and cellular functions, including oxygen transport, cellular growth, and metabolism. Systemic iron homeostasis is predominantly regulated by the liver through the iron regulatory hormone hepcidin. Hepcidin expression is itself regulated by a number of proteins, including transferrin receptor 2 (TFR2). TFR2 has been shown to be expressed in the liver, bone marrow, macrophages, and peripheral blood mononuclear cells. Studies from our laboratory have shown that mice with a hepatocyte-specific deletion of Tfr2 recapitulate the hemochromatosis phenotype of the global Tfr2 knockout mice, suggesting that the hepatic expression of TFR2 is important in systemic iron homeostasis. It is unclear how TFR2 in macrophages contributes to the regulation of iron metabolism. We examined the role of TFR2 in macrophages by analysis of transgenic mice lacking Tfr2 in macrophages by crossing Tfr2(f/f) mice with LysM-Cre mice. Mice were fed an iron-rich diet or injected with lipopolysaccharide to examine the role of macrophage Tfr2 in iron- or inflammation-mediated regulation of hepcidin. Body iron homeostasis was unaffected in the knockout mice, suggesting that macrophage TFR2 is not required for the regulation of systemic iron metabolism. However, peritoneal macrophages of knockout mice had significantly lower levels of ferroportin mRNA and protein, suggesting that TFR2 may be involved in regulating ferroportin levels in macrophages. These studies further elucidate the role of TFR2 in the regulation of iron homeostasis and its role in regulation of ferroportin and thus macrophage iron homeostasis.
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Affiliation(s)
- Gautam Rishi
- Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Eriza S Secondes
- Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and
| | - Daniel F Wallace
- Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - V Nathan Subramaniam
- Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
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38
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Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene 2015; 574:179-92. [PMID: 26456104 PMCID: PMC6660136 DOI: 10.1016/j.gene.2015.10.009] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/04/2015] [Accepted: 10/06/2015] [Indexed: 01/05/2023]
Abstract
The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, AL, USA and Department of Medicine; University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Corwin Q Edwards
- Department of Medicine, Intermountain Medical Center and University of Utah, Salt Lake City, UT, USA.
| | - Ronald T Acton
- Southern Iron Disorders Center, Birmingham, AL, USA and Department of Medicine; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Puukila S, Bryan S, Laakso A, Abdel-Malak J, Gurney C, Agostino A, Belló-Klein A, Prasad K, Khaper N. Secoisolariciresinol diglucoside abrogates oxidative stress-induced damage in cardiac iron overload condition. PLoS One 2015; 10:e0122852. [PMID: 25822525 PMCID: PMC4379144 DOI: 10.1371/journal.pone.0122852] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/23/2015] [Indexed: 02/07/2023] Open
Abstract
Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG), a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-α, interleukin-10 and interferon γ, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload.
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Affiliation(s)
- Stephanie Puukila
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada
| | - Sean Bryan
- Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada
| | - Anna Laakso
- Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada
| | | | - Carli Gurney
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada
| | - Adrian Agostino
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada
| | - Adriane Belló-Klein
- Department of Physiology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Neelam Khaper
- Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada
- * E-mail:
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40
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Bu JT, Bartnikas TB. The use of hypotransferrinemic mice in studies of iron biology. Biometals 2015; 28:473-80. [PMID: 25663418 DOI: 10.1007/s10534-015-9833-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 02/04/2015] [Indexed: 12/15/2022]
Abstract
The hypotransferrinemic (hpx) mouse is a model of inherited transferrin deficiency that originated several decades ago in the BALB/cJ mouse strain. Also known as the hpx mouse, this line is almost completely devoid of transferrin, an abundant serum iron-binding protein. Two of the most prominent phenotypes of the hpx mouse are severe anemia and tissue iron overload. These phenotypes reflect the essential role of transferrin in iron delivery to bone marrow and regulation of iron homeostasis. Over the years, the hpx mouse has been utilized in studies on the role of transferrin, iron and other metals in a variety of organ systems and biological processes. This review summarizes the lessons learned from these studies and suggests possible areas of future exploration using this versatile yet complex mouse model.
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Affiliation(s)
- Julia T Bu
- Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, RI, 02912, USA
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41
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Chen J, Enns CA. CD81 promotes both the degradation of transferrin receptor 2 (TfR2) and the Tfr2-mediated maintenance of hepcidin expression. J Biol Chem 2015; 290:7841-50. [PMID: 25635054 DOI: 10.1074/jbc.m114.632778] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Mutations in transferrin receptor 2 (TfR2) cause a rare form of the hereditary hemochromatosis, resulting in iron overload predominantly in the liver. TfR2 is primarily expressed in hepatocytes and is hypothesized to sense iron levels in the blood to positively regulate the expression of hepcidin through activation of the BMP signaling pathway. Hepcidin is a peptide hormone that negatively regulates iron egress from cells and thus limits intestinal iron uptake. In this study, a yeast two-hybrid approach using the cytoplasmic domain of TfR2 identified CD81 as an interacting protein. CD81 is an abundant tetraspanin in the liver. Co-precipitations of CD81 with different TfR2 constructs demonstrated that both the cytoplasmic and ecto-transmembrane domains of TfR2 interact with CD81. Knockdown of CD81 using siRNA significantly increased TfR2 levels by increasing the half-life of TfR2, indicating that CD81 promotes degradation of TfR2. Previous studies showed that CD81 is targeted for degradation by GRAIL, an ubiquitin E3 ligase. Knockdown of GRAIL in Hep3B-TfR2 cells increased TfR2 levels, consistent with inhibition of CD81 ubiquitination. These results suggest that down-regulation of CD81 by GRAIL targets TfR2 for degradation. Surprisingly, knockdown of CD81 decreased hepcidin expression, implying that the TfR2/CD81 complex is involved in the maintenance of hepcidin mRNA. Moreover, knockdown of CD81 did not affect the stimulation of hepcidin expression by BMP6 but increased both the expression of ID1 and SMAD7, direct targets of BMP signaling pathway, and the phosphorylation of ERK1/2, indicating that the CD81 regulates hepcidin expression differently from the BMP and ERK1/2 signaling pathways.
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Affiliation(s)
- Juxing Chen
- From the Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239
| | - Caroline A Enns
- From the Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239
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42
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Saini RK, Manoj P, Shetty NP, Srinivasan K, Giridhar P. Dietary iron supplements and Moringa oleifera leaves influence the liver hepcidin messenger RNA expression and biochemical indices of iron status in rats. Nutr Res 2014; 34:630-8. [PMID: 25150122 DOI: 10.1016/j.nutres.2014.07.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 05/07/2014] [Accepted: 07/01/2014] [Indexed: 12/21/2022]
Abstract
In this study, the effects of iron depletion and repletion on biochemical and molecular indices of iron status were investigated in growing male Wistar rats. We hypothesized that iron from Moringa leaves could overcome the effects of iron deficiency and modulate the expression of iron-responsive genes better than conventional iron supplements. Iron deficiency was induced by feeding rats an iron-deficient diet for 10 weeks, whereas control rats were maintained on an iron-sufficient diet (35.0-mg Fe/kg diet). After the depletion period, animals were repleted with different source of iron, in combination with ascorbic acid. Iron deficiency caused a significant (P < .05) decrease in serum iron and ferritin levels by 57% and 40%, respectively, as compared with nondepleted control animals. Significant changes in the expression (0.5- to100-fold) of liver hepcidin (HAMP), transferrin, transferrin receptor-2, hemochromatosis type 2, ferroportin 1, ceruloplasmin, and ferritin-H were recorded in iron-depleted and iron-repleted rats, as compared with nondepleted rats (P < .05). Dietary iron from Moringa leaf was found to be superior compared with ferric citrate in overcoming the effects of iron deficiency in rats. These results suggest that changes in the relative expression of liver hepcidin messenger RNA can be used as a sensitive molecular marker for iron deficiency.
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Affiliation(s)
- R K Saini
- Plant Cell Biotechnology Department, CSIR-Central Food Technological Research Institute, Mysore 570 020, India
| | - P Manoj
- Plant Cell Biotechnology Department, CSIR-Central Food Technological Research Institute, Mysore 570 020, India
| | - N P Shetty
- Plant Cell Biotechnology Department, CSIR-Central Food Technological Research Institute, Mysore 570 020, India
| | - K Srinivasan
- Biochemistry & Nutrition Department, CSIR-Central Food Technological Research Institute, Mysore 570 020, India
| | - P Giridhar
- Plant Cell Biotechnology Department, CSIR-Central Food Technological Research Institute, Mysore 570 020, India.
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43
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Silvestri L, Nai A, Pagani A, Camaschella C. The extrahepatic role of TFR2 in iron homeostasis. Front Pharmacol 2014; 5:93. [PMID: 24847265 PMCID: PMC4019842 DOI: 10.3389/fphar.2014.00093] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 04/14/2014] [Indexed: 12/14/2022] Open
Abstract
Transferrin receptor 2 (TFR2), a protein homologous to the cell iron importer TFR1, is expressed in the liver and erythroid cells and is reported to bind diferric transferrin, although at lower affinity than TFR1. TFR2 gene is mutated in type 3 hemochromatosis, a disorder characterized by iron overload and inability to upregulate hepcidin in response to iron. Liver TFR2 is considered a sensor of diferric transferrin, possibly in a complex with hemochromatosis protein. In erythroid cells TFR2 is a partner of erythropoietin receptor (EPOR) and stabilizes the receptor on the cell surface. However, Tfr2 null mice as well as TFR2 hemochromatosis patients do not show defective erythropoiesis and tolerate repeated phlebotomy. The iron deficient Tfr2-Tmprss6 double knock out mice have higher red cells count and more severe microcytosis than the liver-specific Tfr2 and Tmprss6 double knock out mice. TFR2 in the bone marrow might be a sensor of iron deficiency that protects against excessive microcytosis in a way that involves EPOR, although the mechanisms remain to be worked out.
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Affiliation(s)
- Laura Silvestri
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele Milan, Italy
| | - Antonella Nai
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele Milan, Italy
| | - Alessia Pagani
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele Milan, Italy
| | - Clara Camaschella
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele Milan, Italy
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44
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Worthen CA, Enns CA. The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body. Front Pharmacol 2014; 5:34. [PMID: 24639653 PMCID: PMC3944196 DOI: 10.3389/fphar.2014.00034] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 02/18/2014] [Indexed: 12/22/2022] Open
Abstract
Fine-tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron sensor, transferrin receptor 2 (TfR2), is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH). With the loss of functional TfR2, the liver produces about 2-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin (Tf) in the bloodstream, and hepatocytes treated with Tf respond with a 2-fold increase in hepcidin expression through stimulation of the bone morphogenetic protein (BMP)-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.
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Affiliation(s)
- Christal A Worthen
- Department of Cell and Developmental Biology, Oregon Health and Science University Portland, OR, USA
| | - Caroline A Enns
- Department of Cell and Developmental Biology, Oregon Health and Science University Portland, OR, USA
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45
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Frazer DM, Anderson GJ. The regulation of iron transport. Biofactors 2014; 40:206-14. [PMID: 24132807 DOI: 10.1002/biof.1148] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 09/02/2013] [Accepted: 09/06/2013] [Indexed: 01/01/2023]
Abstract
Iron is an essential nutrient, but its concentration and distribution in the body must be tightly controlled due to its inherent toxicity and insolubility in aqueous solution. Living systems have successfully overcome these potential limitations by evolving a range of iron binding proteins and transport systems that effectively maintain iron in a nontoxic and soluble form for much, if not all, of its time within the body. In the circulation, iron is transported to target organs bound to the serum iron binding protein transferrin. Individual cells modulate their uptake of transferrin-bound iron depending on their iron requirements, using both transferrin receptor 1-dependent and independent pathways. Once inside the cell, iron can be chaperoned to sites of need or, if in excess, stored within ferritin. Iron is released from cells by the iron export protein ferroportin1, which requires the ferroxidase activity of ceruloplasmin or hephestin to load iron safely onto transferrin. The regulation of iron export is controlled predominantly at the systemic level by the master regulator of iron homeostasis hepcidin. Hepcidin, in turn, responds to changes in body iron demand, making use of a range of regulatory mechanisms that center on the bone morphogenetic protein signaling pathway. This review provides an overview of recent advances in the field of iron metabolism and outlines the key components of the iron transport and regulation systems.
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Affiliation(s)
- David M Frazer
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia
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46
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A systems biology approach to iron metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 844:201-25. [PMID: 25480643 DOI: 10.1007/978-1-4939-2095-2_10] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Iron is critical to the survival of almost all living organisms. However, inappropriately low or high levels of iron are detrimental and contribute to a wide range of diseases. Recent advances in the study of iron metabolism have revealed multiple intricate pathways that are essential to the maintenance of iron homeostasis. Further, iron regulation involves processes at several scales, ranging from the subcellular to the organismal. This complexity makes a systems biology approach crucial, with its enabling technology of computational models based on a mathematical description of regulatory systems. Systems biology may represent a new strategy for understanding imbalances in iron metabolism and their underlying causes.
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47
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Abstract
The iron hormone hepcidin and its receptor and cellular iron exporter ferroportin control the major fluxes of iron into blood plasma: intestinal iron absorption, the delivery of recycled iron from macrophages, and the release of stored iron from hepatocytes. Because iron losses are comparatively very small, iron absorption and its regulation by hepcidin and ferroportin determine total body iron content. Hepcidin is in turn feedback-regulated by plasma iron concentration and iron stores, and negatively regulated by the activity of erythrocyte precursors, the dominant consumers of iron. Hepcidin and ferroportin also play a role in host defense and inflammation, and hepcidin synthesis is induced by inflammatory signals including interleukin-6 and activin B. This review summarizes and discusses recent progress in molecular characterization of systemic iron homeostasis and its disorders, and identifies areas for further investigation.
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48
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Patel N, Varghese J, Masaratana P, Latunde-Dada GO, Jacob M, Simpson RJ, McKie AT. The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels. Br J Haematol 2013; 164:586-96. [PMID: 24236640 PMCID: PMC4232863 DOI: 10.1111/bjh.12649] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 09/30/2013] [Indexed: 12/21/2022]
Abstract
ATOH8 has previously been shown to be an iron-regulated transcription factor, however its role in iron metabolism is not known. ATOH8 expression in HEK293 cells resulted in increased endogenous HAMP mRNA levels as well as HAMP promoter activity. Mutation of the E-box or SMAD response elements within the HAMP promoter significantly reduced the effects of ATOH8, indicating that ATOH8 activates HAMP transcription directly as well as through bone morphogenic protein (BMP) signalling. In support of the former, Chromatin immunoprecipitation assays provided evidence that ATOH8 binds to E-box regions within the HAMP promoter while the latter was supported by the finding that ATOH8 expression in HEK293 cells led to increased phosphorylated SMAD1,5,8 levels. Liver Atoh8 levels were reduced in mice under conditions associated with increased erythropoietic activity such as hypoxia, haemolytic anaemia, hypotransferrinaemia and erythropoietin treatment and increased by inhibitors of erythropoiesis. Hepatic Atoh8mRNA levels increased in mice treated with holo transferrin, suggesting that Atoh8 responds to changes in plasma iron. ATOH8 is therefore a novel transcriptional regulator of HAMP, which is responsive to changes in plasma iron and erythroid activity and could explain how changes in erythroid activity lead to regulation of HAMP.
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Affiliation(s)
- Neeta Patel
- Division of Diabetes and Nutritional Sciences, Kings College London, London, UK
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49
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Abstract
Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system. Iron is an essential nutrient required for healthy life but, in excess, is the cause of debilitating and even fatal conditions. The most common genetic disorder in humans caused by a mutation, haemochromatosis, results in an iron overload in the liver. Indeed, the liver plays a central role in the regulation of iron. Recently, an increasing amount of detail has been discovered about molecules related to iron metabolism, but an understanding of how they work together and regulate iron levels (in healthy people) or fail to do it (in disease) is still missing. We present a mathematical model of the regulation of liver iron metabolism that provides explanations of its dynamics and allows further hypotheses to be formulated and later tested in experiments. Importantly, the model reproduces accurately the healthy liver iron homeostasis and simulates haemochromatosis, showing how the causative mutation leads to iron overload. We investigate how best to control iron regulation and identified reactions that can be targets of new medicines to treat iron overload. The model provides a virtual laboratory for investigating iron metabolism and improves understanding of the method by which the liver senses and controls iron levels.
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50
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Horvathova M, Ponka P, Divoky V. Molecular basis of hereditary iron homeostasis defects. Hematology 2013; 15:96-111. [DOI: 10.1179/102453310x12583347009810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Monika Horvathova
- Department of BiologyPalacky University, Hnevotinska 3, Olomouc 775 15, Czech Republic
| | - Prem Ponka
- Lady Davis Institute for Medical ResearchJewish General Hospital, and Departments of Physiology and Medicine, McGill University, Montreal, Quebec, Canada
| | - Vladimir Divoky
- Department of BiologyFaculty of Medicine Palacky University, Olomouc, Czech Republic, Department of Hemato-oncology, Faculty of Medicine Palacky University, Olomouc, Czech Republic
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