HFE Gene Homeostatic Iron Regulator
Total Page：16
File Type：pdf, Size：1020Kb
Load more
Recommended publications
-
Iron Regulation by Hepcidin
Iron regulation by hepcidin Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns J Clin Invest. 2013;123(6):2337-2343. https://doi.org/10.1172/JCI67225. Science in Medicine Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β- thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload. Find the latest version: https://jci.me/67225/pdf Science in medicine Iron regulation by hepcidin Ningning Zhao, An-Sheng Zhang, and Caroline A. Enns Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA. Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physi- ologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. -
Viewed Under 23 (B) Or 203 (C) fi M M Male Cko Mice, and Largely Unaffected Magni Cation; Scale Bars, 500 M (B) and 50 M (C)
BRIEF COMMUNICATION www.jasn.org Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron Camille Ansermet,* Matthias B. Moor,* Gabriel Centeno,* Muriel Auberson,* † † ‡ Dorothy Zhang Hu, Roland Baron, Svetlana Nikolaeva,* Barbara Haenzi,* | Natalya Katanaeva,* Ivan Gautschi,* Vladimir Katanaev,*§ Samuel Rotman, Robert Koesters,¶ †† Laurent Schild,* Sylvain Pradervand,** Olivier Bonny,* and Dmitri Firsov* BRIEF COMMUNICATION *Department of Pharmacology and Toxicology and **Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland; †Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; ‡Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia; §School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; |Services of Pathology and ††Nephrology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland; and ¶Université Pierre et Marie Curie, Paris, France ABSTRACT Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is crit- leaves.4 Most recently, Legati et al. have ical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the shown an association between genetic kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical polymorphisms in Xpr1 and primary fa- sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the milial brain calcification disorder.5 How- molecular identity of the protein(s) participating in the basolateral Pi efflux remains ever, the role of XPR1 in the maintenance unknown. Evidence has suggested that xenotropic and polytropic retroviral recep- of Pi homeostasis remains unknown. Here, tor 1 (XPR1) might be involved in this process. Here, we show that conditional in- we addressed this issue in mice deficient for activation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi Xpr1 in the nephron. -
Hepcidin Is Not a Marker of Chronic Inflammation in Atherosclerosis Hepcidin Aterosklerozda Kronik Inflamasyonun Bir Göstergesi De¤Ildir
Original Investigation Orijinal Araflt›rma 239 Hepcidin is not a marker of chronic inflammation in atherosclerosis Hepcidin aterosklerozda kronik inflamasyonun bir göstergesi de¤ildir Aytekin O¤uz, Mehmet Uzunlulu, Nezih Hekim* Department of Internal Medicine, Göztepe Training and Research Hospital, ‹stanbul, Turkey *Pakize Tarz› Laboratory, ‹stanbul, Turkey ABSTRACT Objective: To investigate the relationship between atherosclerosis, an inflammatory disease and hepcidin which is reported as an indi- cator of inflammation Methods: A total of 75 subjects between 40 and 70 years of age were included in the study. The patient group consisted of 40 stable pa- tients who had previously experienced an atherosclerotic event (18 women, 22 men; mean age 56.4±7.1 years). There were two control groups. The first control group consisted of 19 healthy subjects (11 women, 8 men; mean age 52.6± 7.4 years), while the second group inc- luded 16 patients (11 women, 5 men; mean age 56.5±9.3 years) with rheumatoid arthritis and anemia (diseased control group). Hepcidin measurement was performed using Hepcidin Prohormone ELISA (Solid Phase Enzyme-Linked Immunosorbent Assay) test kit. Results: Mean serum hepcidin levels were 243.2±48.8 ng/ml, 374.5±86.4 ng/ml, and 234±59.9 ng/ml in the patient group, in diseased cont- rols, and in healthy controls, respectively. Hepcidin levels were higher in diseased controls compared to the patient group and healthy controls (p=0.001). There were no significant differences between the patient group and healthy controls. Conclusion: These findings did not support the hypothesis that hepcidin levels could be increased in atherosclerotic cardiovascular di- seases as a marker of chronic inflammation. -
Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis
Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2246 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Ryan C. Fassnacht 2010 All Rights Reserved Molecular Mechanisms Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Ryan Christopher Fassnacht, B.S. Hampden Sydney University, 2005 M.S. Virginia Commonwealth University, 2010 Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery Virginia Commonwealth University Richmond, Virginia July 9, 2010 Acknowledgement The Author wishes to thank his family and close friends for their support. He would also like to thank the members of the molecular transplant team for their help and advice. This project would not have been possible with out the help of Dr. Valeria Mas and her endearing -
Tfr2, Hfe, and Hjv in the Regulation of Body Iron Homeostasis
TFR2, HFE, AND HJV IN THE REGULATION OF BODY IRON HOMEOSTASIS By Christal Anna Worthen A DISSERTATION Presented to the Department of Cell & Developmental Biology and the Oregon Health and Science University School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 2014 School of Medicine Oregon Health & Science University CERTIFICATE OF APPROVAL ___________________________________ This is to certify that the PhD dissertation of Christal A Worthen has been approved ______________________________________ Caroline Enns, Ph.D., mentor ______________________________________ Peter Mayinger, Ph.D., Chairman ______________________________________ Philip Stork, M.D. ______________________________________ David Koeller, M.D. ______________________________________ Alex Nechiporuk, Ph.D. TABLE OF CONTENTS i List of Figures ii Acknowledgements iv Abbreviations v Abstract: 1 Chapter 1: Introduction 5 Abstract and Introduction 6 Binding partners, regulation, and trafficking of TFR2 9 Disease-causing mutations in TFR2 12 Hepcidin regulation 12 Physiological function of TFR2 15 Current TFR2 models 18 Summary 19 Figure 21 Chapter 2: The cytoplasmic domain of TFR2 is necessary for 22 HFE, HJV, and TFR2 regulation of hepcidin Abstract 23 Capsule & Introduction 24 Materials and Methods 26 Results 32 Figures 41 Discussion 49 Chapter 3: Lack of functional TFR2 results in stress erythropoiesis 53 Introduction 54 Materials and Methods 55 Results 57 Figures 60 Discussion 65 Chapter 4: Conclusions and future directions 67 Appendices Appendix A: Coculture of HepG2 cells reduces hepcidin expression 71 Appendix B: Hfe-/- macrophages handle iron differently 80 Appendix C: Both ZIP14A and ZIP14B are regulated by HFE and iron 91 Appendix D: The cytoplasmic domain of HFE does not interact with 99 ZIP14 loop 2 by yeast-2-hybris References 105 i LIST OF FIGURES Figure Abstract 1: Body iron homeostasis. -
Mitochondrial Iron Homeostasis and Beyond
cells Review Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond Jonathan V. Dietz 1, Jennifer L. Fox 2 and Oleh Khalimonchuk 1,3,4,* 1 Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA; [email protected] 2 Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC 29424, USA; [email protected] 3 Nebraska Redox Biology Center, University of Nebraska, Lincoln, NE 68588, USA 4 Fred and Pamela Buffett Cancer Center, Omaha, NE 68198, USA * Correspondence: [email protected] Abstract: Cellular iron homeostasis and mitochondrial iron homeostasis are interdependent. Mito- chondria must import iron to form iron–sulfur clusters and heme, and to incorporate these cofactors along with iron ions into mitochondrial proteins that support essential functions, including cellular respiration. In turn, mitochondria supply the cell with heme and enable the biogenesis of cytosolic and nuclear proteins containing iron–sulfur clusters. Impairment in cellular or mitochondrial iron homeostasis is deleterious and can result in numerous human diseases. Due to its reactivity, iron is stored and trafficked through the body, intracellularly, and within mitochondria via carefully orchestrated processes. Here, we focus on describing the processes of and components involved in mitochondrial iron trafficking and storage, as well as mitochondrial iron–sulfur cluster biogenesis and heme biosynthesis. Recent findings and the most pressing topics for future research are highlighted. Keywords: iron homeostasis; mitochondrial iron–sulfur clusters; heme biosynthesis; iron trafficking Citation: Dietz, J.V.; Fox, J.L.; Khalimonchuk, O. Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond. Cells 2021, 1. Introduction 10, 2198. https://doi.org/10.3390/ Most iron in vertebrates is used to make heme b cofactors for hemoglobin in red blood cells10092198 cells; however, the essential nature of iron derives from more than this role in oxygen transport through the bloodstream. -
2013 New Molecular CPT Co
Cleveland Clinic Laboratories 2013 New Molecular CPT Codes 2013 Test Name Order Code Billing Code CPT Codes 2012 CPT Codes ACADM PCR, Complete, Tier 2 ACADM 88175 81404 83891, 83894x10, 83898x10, 83904x20 ACTA2 Gene Sequencing ACTA2 88528 81403 83898x9, 83904x9, 83891 ADmark ApoE Genotype (Symptomatic) APOALZ 82397 81401 83892, 83894, 83898, 81401, 83891 ADmark PS-1 Analysis, Symptomatic PS1SY 83019 81405 83904x10, 83909x10, 83898x10, 83891 Alpha Globin (HBA1 and HBA2) Sequencing HBA12 88847 81257 New test in 2013 Alpha Thalassemia Gene Deletion ATHAL 84123 81257 83891, 83900, 83901x8, 83894 Alpha-1-Antitrypsin Quantitation and Phenotyping PHA1A 84187 81332 82103, 82104 Angelman UBE3A Sequencing UBE3A 88200 81331 83898x8, 83904x10, 83909x10 APO E Genotype APOEG 79374 81401 83891, 81401, 83898, 83896x2 ARX Sequence Analysis ARXSEQ 87860 81404 83890, 83898x5, 83894, 83904x6 Autoimmune Polyglandular Syndrome Evaluation AIRE 83293 81479 83909x14, 83891, 83898x14, 83904x14 Autosomal Dom Ataxia Evaluation AUTOAT 82179 81401, 83909x88, 83898x88, 83904x77, 81479x13 83891 Barth Syndrome, Carrier BARCAR 82536 81406 83891, 83898, 83904x2 Barth Syndrome, Initial Patient BARINI 82535 81406 83891, 83898, 83904x9 Bartonella PCR, Tissue TBART 87924 87471 83898x4, 83890, 83894 B-Cell Clonality Using BIOMED-2 PCR Primers BCBMD 87904 81261, 83891, 83900, 83909x5, 83898x3, 83901x2, 81264 83912, 81261, 81264 BCL 2 mbr (PCR) BCL2 81099 81401 81401, 83890, 83898, 83894, 83912 BCR/ABL Kinase Domain Mutation Analysis KINASE 84529 81403 83891, 83898, 83902, 83904x4, -
Hepcidin Therapeutics
pharmaceuticals Review Hepcidin Therapeutics Angeliki Katsarou and Kostas Pantopoulos * Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(514)-340-8260 (ext. 25293) Received: 3 November 2018; Accepted: 19 November 2018; Published: 21 November 2018 Abstract: Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art. Keywords: iron metabolism; hepcidin; ferroportin; hemochromatosis; anemia 1. Systemic Iron Homeostasis Iron is an essential constituent of cells and organisms and participates in vital biochemical activities, such as DNA synthesis, oxygen transfer, and energy metabolism. The biological functions of iron are based on its capacity to interact with proteins and on its propensity to switch between the ferrous (Fe2+) and ferric (Fe3+) oxidation states. -
Hepcidin the Key Regulator of Iron in the Blood St
Hepcidin The Key Regulator of Iron in the Blood St. Dominic Middle School SMART Team Eclaire Jessup, Dominic Kowalik, Allyssa Larcheid, Samuel Larcheid, Claire Lois, Sara Maslowski, I. Introduction to Hepcidin and Iron Homeostasis Emma Pittman, Joseph Platz, Marissa Puccetti, Tyler Shecterle, Nicole Simson, Emma Wenger Abstract Hepcidin, a peptide hormone, is the key regulator of plasma iron levels in humans, and is known to play an important role in Iron is found everywhere on Earth and is essential to life. The human body contains 3-4 grams of iron Teacher: Ms. LaFlamme Mentor: Dr. Matthew S. Karafin, various human diseases, such as hemochromatosis. Hepcidin inhibits the entry of iron into circulation by binding to and over fifty percent is found in red blood cells (RBCs). Without iron, the oxygen carrying protein ferroportin, a trans-membrane iron export channel found primarily on enterocytes, hepatocytes and macrophages where iron Medical College of Wisconsin, The Blood Center of Wisconsin hemoglobin that fills RBCs cannot be made and the bone marrow cannot carry out erythropoiesis is sequestered. When hepcidin binds to ferroportin, both are drawn into the cell by endocytosis and degraded in a lysosome. When hepcidin levels increase, ferroportin levels on cells decrease and iron cannot be released from cells into the blood. (RBC production). All iron in the body is absorbed from the diet in the duodenum. Hepcidin production by the liver is affected by erythropoiesis in bone marrow, blood oxygenation, certain inflammatory The peptide hormone, hepcidin, controls the release of the dietary iron from duodenal enterocytes III. Hepcidin Structure & Function cytokines, intracellular iron storage, and plasma transferrin. -
The Correlation of the Hepcidin Ferritin Ratio and the Severity of Liver Cirrhosis
The Correlation of the Hepcidin Ferritin Ratio and the Severity of Liver Cirrhosis Imelda Rey1,2 *, Rustam Effendi-Ys1,3 and Khairani Sukatendel 4 1 Division of Gastroenterohepatology, Internal Medicine Department, Universitas Sumatera Utara , Medan, Indonesia 2 Adam Malik General Hospital, Medan, Indonesia 3 Pirngadi General Hospital, Medan, Indonesia 4 Department of Obstetric and Gynecology, Universitas Sumatera Utara, Medan, Indonesia Keywords: Hepcidin, Liver Cirrhosis, Severity. Abstract: Background. Hepcidin serum level was influenced by the inflammation and iron deposit in chronic liver disease / CLD), but the correlation between the hepcidin ferritin ratio and the severity of liver cirrhosis was still not clear. The aim of this study was to found correlation between the hepcidin ferritin ratio and the severity of liver cirrhosis. Methods. The study was conducted in Gastroenterohepatology Division, Internal Medicine Department, Faculty of Medicine, University of Sumatera Utara. The study was an analytic comparative, cross sectional study. The subject were liver cirrhosis patients that fulllfiled inclusion criteria and informed consent. Results. From 78 liver cirrhosis patients, mean age was 51.36 ± 12.6 years old. Male was more than female ( 44 (56%), 34 (43.6%), respectively. We found that there was no significant difference of the hepcidin ferritin ratio among Child pugh A , Child pugh B and Child pugh C patients (0.17 ; 0.11 and 0.28, respectively, with p = 0.161). Conclusion. There was no significant difference of the hepcidin ferritin ratio among severity of liver cirrhosis. 1 INTRODUCTION chronic liver disease (CLD), but less is known about the correlation between the ratio of hepcidin : Hepcidin is the hormone of iron which produced in ferritin and the severity of liver cirrhosis. -
Ncomms4301.Pdf
ARTICLE Received 8 Jul 2013 | Accepted 23 Jan 2014 | Published 13 Feb 2014 DOI: 10.1038/ncomms4301 Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism Mikalai Malinouski1,2, Nesrin M. Hasan3, Yan Zhang1,4, Javier Seravalli2, Jie Lin4,5, Andrei Avanesov1, Svetlana Lutsenko3 & Vadim N. Gladyshev1 Trace elements are essential for human metabolism and dysregulation of their homoeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundamental differences in the regulation of different trace elements. Specifically, selenium levels are controlled through the selenocysteine machinery and expression of abundant selenoproteins; copper balance is affected by lipid metabolism and requires machinery involved in protein trafficking and post-translational modifications; and the iron levels are influenced by iron import and expression of the iron/haeme-containing enzymes. Our approach can be applied to a variety of disease models and/or nutritional conditions, and the generated data set opens new directions for studies of human trace element metabolism. 1 Genetics Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 2 Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA. 3 Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA. 4 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. -
Molecular Pathogenesis of Iron Overload Gut: First Published As 10.1136/Gut.51.2.290 on 1 August 2002
290 REVIEW Molecular pathogenesis of iron overload Gut: first published as 10.1136/gut.51.2.290 on 1 August 2002. Downloaded from D Trinder, C Fox, G Vautier, J K Olynyk ............................................................................................................................. Gut 2002;51:290–295 Our current understanding of iron absorption under deficiency.34Iron is then stored in the enterocyte normal conditions is presented, together with an or transferred out across the basolateral mem- brane by a membrane bound protein called ferro- overview of the clinical disorders of iron overload and portin (also known as IREG1 and MTP1).5–7 the molecular processes that contribute to increased iron Extracellular ferrous iron is oxidised by the multi deposition in iron overload. Recently, a number of new copper oxidase haephestin and bound by plasma transferrin.8 genes involved in iron metabolism have been identified The mechanism of absorption of haem iron has which is allowing the molecular mechanisms of iron yet to be elucidated. Transfer across the brush absorption to be elucidated. border membrane is probably mediated by an unidentified haem receptor. Once inside, entero- .......................................................................... cyte iron is released from haem by haem oxygen- ase and either stored or transferred out of the ron homeostasis is controlled by the absorption enterocyte by a mechanism that is likely to be of iron from the diet. It occurs mainly in the similar to that for ionic iron (fig 1).9 Iduodenum at a rate of approximately 1–2 mg iron per day. When iron levels in the body or the REGULATION OF IRON ABSORPTION diet are low, the rate of iron absorption is Iron absorption is regulated by a number of increased, and when iron levels are replete there factors, including the level of body iron stores, the is a reduction in the rate of iron absorption and rate of erythropoiesis, and hypoxia.