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The Roles of Iron in Health and Disease Pauline T Molecular Aspects of Medicine 22 22001) 1±87 www.elsevier.com/locate/mam The roles of iron in health and disease Pauline T. Lieu, Marja Heiskala, Per A. Peterson, Young Yang * The R.W. Johnson Pharmaceutical Research Institute, 3210 Merry®eld Row, San Diego, CA 92121, USA Abstract Iron is vital for almost all living organisms by participating in a wide variety of metabolic processes, including oxygen transport, DNA synthesis, and electron transport. However, iron concentrations in body tissues must be tightly regulated because excessive iron leads to tissue damage, as a result of formation of free radicals. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload and, possibly, to neurodegener- ative diseases. The molecular understanding of iron regulation in the body is critical in identi- fying the underlying causes for each disease and in providing proper diagnosis and treatments. Recent advances in genetics, molecular biology and biochemistry of iron metabolism have as- sisted in elucidating the molecular mechanisms of iron homeostasis. The coordinate control of iron uptake and storage is tightly regulated by the feedback system of iron responsive element- containing gene products and iron regulatory proteins that modulate the expression levels of the genes involved in iron metabolism. Recent identi®cation and characterization of the hemo- chromatosis protein HFE, the iron importer Nramp2, the iron exporter ferroportin1, and the second transferrin-binding and -transport protein transferrin receptor 2, have demonstrated their important roles in maintaining body's iron homeostasis. Functional studies of these gene products have expanded our knowledge at the molecular level about the pathways of iron me- tabolism and have provided valuable insight into the defects of iron metabolism disorders. In addition, a variety of animal models have implemented the identi®cation of many genetic defects that lead to abnormal iron homeostasis and have provided crucial clinical information about the pathophysiology of iron disorders. In this review, we discuss the latest progress in studies of iron metabolism and our current understanding of the molecular mechanisms of iron absorption, transport, utilization, and storage. Finally, we will discuss the clinical presentations of iron metabolism disorders, including secondary iron disorders that are either associated with or the result of abnormal iron accumulation. Ó 2001 Elsevier Science Ltd. All rights reserved. Keywords: Heme; Hemochromatosis; HFE; Iron responsive element; Iron transporter; Transferrin receptor * Corresponding author. Tel: +1-858-450-2023. E-mail address: [email protected] 2Y. Yang). 0098-2997/01/$ - see front matter Ó 2001 Elsevier Science Ltd. All rights reserved. PII: S0098-2997200)00006-6 2 P.T. Lieu et al. / Molecular Aspects of Medicine 22 /2001) 1±87 Contents 1. Introduction . 4 2. Regulation of iron uptake and storage . 7 2.1. Iron-mediated feedback regulation . 7 2.2. The iron responsive element-binding proteins: iron regulatory proteins . 10 2.3. Regulation of iron regulatory proteins by oxidative stress. 11 2.4. The iron store proteins: ferritin heavy and light chains. 12 2.5. Iron regulatory proteins and neurological diseases . 13 2.6. Iron responsive element-associated diseases . 13 3. Dietary iron absorption . 14 3.1. Non-heme iron uptake . 14 3.2. The iron importer: Nramp2 . 15 3.3. Heme iron uptake. 16 3.4. Paraferritin-mediated iron uptake. 17 3.5. The iron exporter: ferroportin1 . 17 3.6. Regulation of dietary iron absorption. 18 4. Transferrin receptor-mediated iron uptake . 18 4.1. The iron-binding and -transport protein: transferrin. 19 4.2. The transferrin-binding and -transport protein: transferrin receptor 1 . 19 4.3. Expression of transferrin receptor 1 . 22 4.4. Function of transferrin receptor 1 . 25 4.5. Second transferrin-binding and -transport protein: transferrin receptor 2 . 27 4.6. Transferrin receptors in disease development . 28 5. The hemochromatosis protein HFE in iron metabolism . 29 5.1. The hemochromatosis gene: Hfe. 30 5.2. The hemochromatosis protein: HFE . 32 5.3. Regulation of HFE . 33 5.4. Physical association of HFE and transferrin receptor 1 . 33 5.5. Consequence of the HFE-transferrin receptor 1 interaction. 36 6. Additional factors involved in iron metabolism . 37 6.1. The multi-copper oxidase: ceruloplasmin. 38 6.2. The hypoxia responsive element-binding protein: hypoxia-inducible factor-1 . 39 6.3. The Friedreich's ataxia protein: frataxin . 39 6.4. The transferrin-like iron-binding protein: melanotransferrin . 40 6.5. The stimulator of iron transport protein . 40 6.6. The Menkes' and Wilson's disease proteins: ATPase 7A and 7B . 41 7. Iron metabolism disorders in animals . 42 7.1. Transferrin receptor 1-de®cient mice. 42 7.2. Hypotransferrinemic Trfhpx=hpx mice. 43 7.3. Microcytic anemic mk/mk mice . 44 7.4. Belgrade 2b/b) anemic rat. 45 7.5. Sex-linked anemic 2sla/sla) mice . 45 P.T. Lieu et al. / Molecular Aspects of Medicine 22 /2001) 1±87 3 7.6. -thalassemic Hbbd2th3)/Hbbd2th3) mice. 46 7.7. -thalassemic mice. 47 7.8. Aceruloplasminemic ceruloplasmin-de®cient mice . 47 7.9. 2 microglobulin-de®cient mice. 47 7.10. Hemochromatosis Hfe-de®cient mice. 48 7.11. T-cell receptor -de®cient mice . 50 7.12. Recombination-activating gene 1-de®cient mice . 50 7.13. Compound mutant mice . 51 8. Diagnosis of human iron disorders . 51 8.1. Parameters for diagnosing iron de®ciency . 52 8.2. Parameters for diagnosing iron overload . 52 9. Iron metabolism disorders in humans . 53 9.1. Defects in iron absorption . 54 9.1.1. Hereditary hemochromatosis . 54 9.1.2. HFE3-type hemochromatosis . 56 9.1.3. Juvenile hemochromatosis . 56 9.1.4. African dietary iron overload . 56 9.1.5. Iron de®ciency-induced anemia . 57 9.2. Defects in iron transport . 57 9.2.1. Porphyria cutanea tarda. 57 9.2.2. Erythropoietic protoporphyria . 57 9.2.3. Familial hypoferremic microcytic anemia syndrome . 58 9.2.4. Congenital dyserythropoietic anemias . 58 9.2.5. Aceruloplasminemia . 59 9.2.6. Wilson's disease . 59 9.2.7. Menkes, disease. 60 9.2.8. Sideroblastic anemias. 60 9.2.9. Sideroblastic anemia and ataxia . 61 9.2.10. Friedreich's ataxia. 61 9.2.11. Hyperferritinemia with autosomal-dominant congenital cataract . 61 9.2.12. Atransferrinemia . 61 9.3. Secondary iron disorders . 62 9.3.1. Chronic in¯ammation-associated anemia . 62 9.3.2. Alcohol-induced iron abnormalities. 63 9.3.3. Chronic hepatitis C . 63 9.3.4. Tumorigenesis . 63 9.3.5. Neurodegenerative diseases. 64 9.3.5.1. Parkinson's disease . 64 9.3.5.2. Hallervorden±Spatz syndrome . 65 9.3.5.3. Alzheimer's disease. 65 9.3.5.4. Huntington's disease. 66 10. Conclusions and future perspectives . 66 References . 69 4 P.T. Lieu et al. / Molecular Aspects of Medicine 22 /2001) 1±87 1. Introduction Iron represents approximately 35 and 45 mg/kg of body weight in adult women and men, respectively 2Andrews, 1999a,b; Bothwell et al., 1995). The majority of total body iron, about 60±70%, is present in hemoglobin in circulating erythrocytes. Another 10% of essential body iron is present in the forms of myoglobins, cyto- chromes, and iron-containing enzymes, amounting to no more than 4±8 mg of iron. In healthy individual, the remaining 20±30% of surplus iron is stored as ferritins and hemosiderins in hepatocytes and reticuloendothelial macrophages 2Conrad et al., 1999). Even though the amount of iron bound to transferrin is less than 1% 2approxi- mately 4 mg) of the total body iron store, it is the most signi®cant iron pool and has the.
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