Responses to iron ingestion Simulations of the iron ingestion experiment conducted on healthy human subjects by Girelli et al [ 50 ] incorporate all parameter values estimated via different perturbations and experiments e.
Application and limitations of experimental data With this global model involving a large number of variables and parameters and limited experimental data, the model validation process cannot be exhaustive. Single vs ensemble predictions In the simulation of CKD with treatments, only the best calibrated model was used for all simulations. Conclusion and future studies This multi-scale, whole-body model of iron metabolism not only simulates data from a wide range of experimental studies, but also predicts novel responses that have not been observed.
Supporting information. S1 Fig. Pharmacokinetic model incorporating absorption, distribution and elimination of rhHepc and rEpo. S2 Fig. S3 Fig. S4 Fig. Comparison of the model output solid line vs. S5 Fig. S6 Fig. S7 Fig. Represents model simulation of development of anemia of chronic kidney disease.
S1 Data. References 1. Brock JH. Iron Metabolism in Health and Disease. London: W. Saunders Company Ltd; Iron metabolism. Curr Opin Chem Biol.
Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol. Wessling-Resnick M. Biochemistry of iron uptake.
Aisen P, Listowsky I. Iron transport and storage proteins. Annu Rev Biochem. Marshall A. Lichtman EB, Thomas J. Prchal Williams Hematology. Epub 7th edition. Greer JP. Wintrobe's Clinical Hematology. Andrews NC. Disorders of iron metabolism. N Engl J Med. Richardson DR. Role of ceruloplasmin and ascorbate in cellular iron release. J Lab Clin Med. Role of ceruloplasmin in cellular iron uptake.
Role of ceruloplasmin in macrophage iron efflux during hypoxia. J Biol Chem. Unexpected role of ceruloplasmin in intestinal iron absorption.
Cell Metab. Hepcidin in iron overload disorders. Hepcidin is decreased in TFR2 hemochromatosis. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation.
Hepcidin—a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. A mathematical model of iron metabolism. J Math Biol. Mathematical modeling of the dynamic storage of iron in ferritin.
BMC Syst Biol. Mitchell S, Mendes P. A computational model of liver iron metabolism. PLoS Comput Biol. Computational modeling and analysis of iron release from macrophages. Osaki S. Kinetic studies of ferrous ion oxidation with crystalline human ferroxidase ceruloplasmin. Osaki S, Johnson DA.
Mobilization of liver iron by ferroxidase ceruloplasmin. Hematopoietic model with moving boundary condition and state dependent delay: applications in erythropoiesis. J Theor Biol. Dynamical modelling of haematopoiesis: an integrated view over the system in homeostasis and under perturbation. J R Soc Interface. Model predictive control of erythropoietin administration in the anemia of ESRD.
Am J Kidney Dis. Model predictive control with reinforcement learning for drug delivery in renal anemia management. Determining optimum hemoglobin sampling for anemia management from every-treatment data. Clin J Am Soc Nephrol. Zalunardo N, Levin A. Anemia and the heart in chronic kidney disease. Semin Nephrol. Spiegel DM.
Anemia management in chronic kidney disease: what have we learned after 17 years? Semin Dial. Erythropoietin: biology and clinical use. Hematol Oncol Clin North Am. Hayat A. Safety issues with intravenous iron products in the management of anemia in chronic kidney disease. Clin Med Res. Erythropoietin stimulating agents in the management of anemia of chronic kidney disease. Patient Prefer Adherence. Iron, inflammation, dialysis adequacy, nutritional status, and hyperparathyroidism modify erythropoietic response.
An indistinct balance: the safety and efficacy of parenteral iron therapy. J Am Soc Nephrol. Eaton JW, Qian M. Molecular bases of cellular iron toxicity. Free Radic Biol Med. Age-structured and two-delay models for erythropoiesis. Math Biosci. A biomathematical model of human erythropoiesis under erythropoietin and chemotherapy administration.
PLoS One. Interaction of human diferric transferrin with reticulocytes. Iron loading and erythrophagocytosis increase ferroportin 1 FPN1 expression in J macrophages.
J Hepatol. Moore E, Bellomo R. Erythropoietin EPO in acute kidney injury. Ann Intensive Care. Guyton and Hall Textbook of Medical Physiology. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol Jelkmann W.
Regulation of erythropoietin production. J Physiol. Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo. Hepcidin expression and iron transport in alveolar macrophages. Arosio P. New signaling pathways for hepcidin regulation. P, W RRK. IMA Research. Iron transport.
Annu Rev Nutr. Role of transferrin in determining internal iron distribution. Human transferrin. The figure below summarizes the potential uses of iron recycled from red blood cells. Iron is unique among minerals in that our body has limited excretion ability.
Thus, absorption is controlled by the hormone hepcidin. The liver has an iron sensor so when iron levels get high, this sensor signals for the release of hepcidin. Hepcidin causes degradation of ferroportin. Thus, the iron is not able to be transported into circulation 5. The iron is now trapped in the enterocyte, which is eventually sloughed off and excreted in feces.
Thus, iron absorption is decreased through the action of hepcidin. Figure Iron homeostasis in host defence and inflammation. Nat Rev Immunol.
Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. Finch C. Regulators of iron balance in humans. Transferrin receptor distribution and regulation in the rat small intestine. Effect of iron stores and erythropoiesis. Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs. Am J Physiol. Milman N. Iron prophylaxis in pregnancy—general or individual and in which dose?
Ann Hematol. Schroeder BO , Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am J Clin Nutr. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants.
Nutritional iron deficiency. Beard JL , Durward C. Iron physiology and pathophysiology in humans.. New York : Springer ; Google Preview. Diagnosis and management of iron deficiency anaemia: a clinical update. Med J Aust. Iron deficiency anaemia. Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin. Anderson GJ. Mechanisms of iron loading and toxicity. Am J Hematol.
HFE gene: structure, function, mutations, and associated iron abnormalities. Deugnier Y , Turlin B. Iron physiology and pathophysiology in humans. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease.
Cystic fibrosis: ironing out the problem of infection? Metals, oxidative stress and neurodegeneration: a focus on iron, manganese and mercury. Neurochem Int. Management of the thalassemias. Cold Spring Harb Perspect Med. Small cyclic agonists of iron regulatory hormone hepcidin. Bioorg Med Chem Lett. Arezes J , Nemeth E. Hepcidin and iron disorders: new biology and clinical approaches.
Int J Lab Hematol. Weiss G , Goodnough LT. Anemia of chronic disease. A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Current understanding of iron homeostasis. Lucia, Queensland, Australia. Oxford Academic. David M Frazer. Select Format Select format. Permissions Icon Permissions. ABSTRACT Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron concentrations within the optimal physiologic range.
Open in new tab Download slide. Definition of structure and function relations of proteins of mammalian iron metabolism Structural information on many iron-related proteins and particularly membrane transporters is grossly inadequate. Intracellular iron trafficking and homeostasis Identifying and studying the role of intracellular iron chaperones and iron delivery to key organelles e.
Relations between iron and other metals Some links are widely appreciated e. Regulation of genes encoding iron-related proteins Important regulatory mechanisms are well known e. Factors regulating hepcidin Some pathways are well defined, but others, such as the roles played by HFE and TfR2, require delineation.
Consequences of supraphysiologic iron intake Defining the effects of supplementation of iron-replete individuals has important practical implications.
Organ-specific iron homeostasis Different organs and different cell types within organs handle iron differently, and our understanding in this area remains limited. Prioritization of iron supply to different organs Some tissues are relatively protected from ID or relatively susceptible to iron loading.
Understanding the mechanisms underlying this phenomenon is important. Links between iron and the microbiome How iron alters the gut microbiome and potentially those of other sites is an important consideration in any studies of supplementation, and the microbial community composition could affect body iron physiology. New indicators and combinations of indicators Recent molecular advances might be useful to identify new iron-status indicators or new combinations of indicators.
Inflammation Inflammation remains a major influence on key measures of iron status, and how it is taken into account is an important issue. This is increasingly a problem as the level of obesity in the community rises. Genetic profile Genetic influences on iron status and new genetic modifiers continue to be identified. Consideration of genetic profiling may be useful to assess the risk of iron-related disorders and the response to treatment.
Iron removal The suite of clinically approved iron chelators remains very limited, and better compounds and more efficient delivery methods are needed. Personalized medicine and nutrition Contemporary genetic and physiologic knowledge might be used to tailor iron-related treatments whether they be iron supplementation, iron redistribution, or iron removal to individuals, specific life stages, or specific clinical conditions more effectively.
Open in new tab. Google Scholar Crossref. Search ADS. Medicine — Fisher J et al Ferritin a novel mechanism for delivery of iron to the brain and other organs.
Fleming RE et al Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Mov Disord — J Nutr s—s. Garrick M et al Iron supplementation moderates but does not cure the Belgrade anemia. Biometals — Placenta — Goswami T, Andrews NC Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing.
Green R et al Body iron excretion in man: a collaborative study. Am J Med — J Cell Physiol — Gunshin H et al Cloning and characterization of a mammalian proton-coupled metal-ion transporter. J Clin Investig — Han O, Kim EY Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells.
J Cell Biochem — Cell — Hodgson E, Juchau MR Ligand binding to human placental cytochrome P interaction of steroids and heme-binding ligands. J Steroid Biochem — Huwyler J, Pardridge WM Examination of blood-brain barrier transferrin receptor by confocal fluorescent microscopy of unfixed isolated rat brain capillaries. Jiang R et al Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain.
Electron Microsc Rev — King BF Localization of transferrin on the surface of the human placenta by electron microscopic immunocytochemistry. Biochemistry — Lane RS Regulating factors in the transfer of iron across the rat placenta. J Mol Biol — Levine DS, Woods JW Immunolocalization of transferrin and transferrin receptor in mouse small intestinal absorptive cells. Journal Histochem Cytochem — Cell Biochem Funct — Biochim Biophys Acta — Iron uptake at the apical membrane in the intestine.
J Neurol Sci — FEBS Lett — J Reprod Fertil — Proc Nutr Soc — McCarthy RC, Kosman DJ Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux. McCarthy RC, Kosman DJ Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. PloS One 9:e McKie AT et al An iron-regulated ferric reductase associated with the absorption of dietary iron.
Science — Brain Imaging Behav. J Med Genet — Gut — Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled study in Danish women. Dan Med Bull — Moos T, Morgan EH a Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. Moos T, Skjoerringe T, Gosk S, Morgan EH Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1.
Biochim et Biophys Acta — Nemeth E Iron regulation and erythropoiesis. Curr Opin Hematol — Nemeth E et al Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing Its internalization. Nielsen JE, Jensen LN, Krabbe K Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome.
J Neurol Neurosurg Psychiatr — Oates PS, Morgan EH Ferritin gene expression and transferrin receptor activity in intestine of rats with varying iron stores. Am J Physiol G—G Radiology — Am J Obstet Gynecol — J Pharmacol Exp Ther — Parkkila S et al Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis.
Patel BN, David S A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. Piperno A et al Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Am J Med Genet B b— Article Google Scholar. Qian ZM et al Development and iron-dependent expression of hephaestin in different brain regions of rats. Qiu AD et al Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.
Proc Natl Acad Sci — J Neurol — Shayeghi M et al Identification of an intestinal heme transporter Cell — Sheldon JH Hemochromatosis. Oxford University Press, London, pp — Pediatr Res — J Pathol — Simpson IA et al A novel model for brain iron uptake: introducing the concept of regulation. Front Mol Neurosci Smith MW, Gumbleton M Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies.
J Drug Target — Best Pract Res Clin Haematol — Strazielle N, Ghersi-Egea JF Physiology of blood-brain interfaces in relation to brain disposition of small compounds and macromolecules. Svanberg B Iron absorption in early pregnancy—a study of the absorption of non-haeme iron and ferrous iron in early pregnancy. Acta Obstet et Gynecol Scand Suppl — Acta Obstet et Gynecol Scand — Tsunoo H, Sussman HH Characterization of transferrin binding and specificity of the placental transferrin receptor.
Arch Biochem Biophys — Waheed A et al Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. West AR, Oates PS Subcellular location of heme oxygenase 1 and 2 and divalent metal transporter 1 in relation to endocytotic markers during heme iron absorption.
J Gastroenterol Hepatol — PubMed Google Scholar. Wong CT, Saha N Inter-relationships of storage iron in the mother, the placenta and the newborn. Acta Obstet Gynecol Scand — Am J Physiol C—C Yang WM et al Transient expression of iron transport proteins in the capillary of the developing rat brain.
Cell Mol Neurobiol — Gastroenterology U—U Yoshikawa T, Pardridge WM Biotin delivery to brain with a covalent conjugate of avidin and a monoclonal antibody to the transferrin receptor. Nat Rev Neurosci — Rev Neurosci — Download references. You can also search for this author in PubMed Google Scholar. Correspondence to James R. Reprints and Permissions.
Duck, K. Iron uptake and transport across physiological barriers. Biometals 29, — Download citation. Received : 07 July Accepted : 09 July Published : 25 July Issue Date : August Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.
Skip to main content. Search SpringerLink Search. Download PDF. Abstract Iron is an essential element for human development. Introduction Iron Fe is an essential, multifunctional micronutrient that has been shown to function in oxygen transport through its role in hemoglobin, as a crucial cofactor in the electron transport chain, and as a cofactor during DNA synthesis Beard et al.
Iron transport in the duodenum The gut functions as the key modulator of iron concentration in the body. Full size image. Iron transport across the placenta The placenta serves as the interface between mother and fetus. Mechanism of iron transport at the placenta The process of iron transport at the placenta is unlike the mechanism seen in the gut Fig.
Table 1 Brain disorders associated with brain iron accumulation or brain iron deficiency Full size table.
0コメント