The gene hfe, which contains two missense mutations c282y and h63d, was recently identified. Iron overload may lead also to insulin resistance and diabetes. For instance, iron metabolism posttranscriptional regulation is mediated by both specific systems that regulate mrna stability. An overview of molecular basis of iron metabolism regulation. The gene hfe, which contains two missense mutations c282y and h63d, was recently identified objective. The tissue distribution of hfe offers few clues to its role in iron metabolism, because hfe is broadly expressed 12. However, iron depletive therapy targets only iron excess and alternative. The hfe gene has three common mutations, c282y, h63d and s65c. Our current knowledge of iron metabolism and related disorders photis beris md, isabelle tchou hematology service, geneva university hospitals, geneva, isvicre i. If hfe acts in conjunction with fpn1 to decrease iron efflux from cells, it raises the question of why hepatocytes lacking hfe accumulate iron. Besides the systemic regulation of iron metabolism mediated by hepcidin. This is second part of the iron metabolism, in the first part we discussed about the intake and transport of iron through out our body and now in this lecture we have discussed the storage and. However, in vivo, hfe is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively. However, as the beneficial effect of hfe mutations on iron metabolism in chd does not seem to be fully explained by lower hepcidin levels, and hepcidin might also play a beneficial antiinflammatory and antimicrobic action during sepsis, direct inhibition of hfemediated regulation of iron metabolism may represent a valuable alternative.
Yet iron can be potentially toxic due its ability to. Sep 17, 2018 this is second part of the iron metabolism, in the first part we discussed about the intake and transport of iron through out our body and now in this lecture we have discussed the storage and. Identification of hfe, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as tfr2, that are important in nonhfeassociated iron overload. This study shows that hfe expressed in the duodenum does not play a primary role in iron homeostasis. The role of hfe mutations on iron metabolism in beta.
Iron is an essential element in all living organisms and is required as a cofactor for oxygenbinding proteins. The mechanisms of systemic iron homeostasis and etiology. Our current knowledge of iron metabolism and related. Anderson1,2 1iron metabolism laboratory, queensland institute of medical research, brisbane, queensland, australia 2school of medicine, university of queensland, brisbane, queensland, australia summary the intestinal absorption of the essential trace element iron and. These act through proteins on the hepatocyte plasma membrane such as hfe, hemojuvelin and transferrin receptor 2 to alter transcription of the hepcidin gene. It is also the prosthetic group of a number of enzymes such as redox cytochromes and the p450 class of detoxifying cytochromes. Iron needs to be tightly regulated, as iron insufficiency induces a hypoferric anemia in mammals, coupled to hypoxia in. However, as the beneficial effect of hfe mutations on iron metabolism in chd does not seem to be fully explained by lower hepcidin levels, and hepcidin might also play a beneficial antiinflammatory and antimicrobic action during sepsis, direct inhibition of hfe mediated regulation of iron metabolism may represent a valuable alternative. Nov 26, 2018 iron metabolism must be tightly controlled in order to avoid deleterious situations, including iron overload diseases, especially hfe related hemochromatosis. Iron metabolism disorders most common form of anemia. Liver transplantation normalizes serum hepcidin level and. Indeed, gene transfer experiments, comparing mutant and wildtype hfe cdnas, demonstrated that the mutant fails to interact with.
Pdf the role of hfe mutations on iron metabolism in beta. Pdf iron metabolism and disease kostas pantopoulos. Therefore, the present study aimed to 1 evaluate the role of the liver in regulating iron metabolism, based on the longterm evolution of iron metabolism after lt in patients homozygous for hfe c282y. This puts hfe directly in the midst of iron metabolism because tfr is responsible for cellular uptake of iron bound transferrin. Hfe haemochromatosis is rare and acquired iron overload is common, careful. Andreas erhardt 1, arne hoffmann 1, harald hefter 2 and. Baishideng publishing group inc, 7041 koll center parkway, suite 160, pleasanton, ca 94566, usa. The aim of this study was to evaluate the prevalence of hfe mutations and their effect on iron metabolism in italian celiac patients at diagnosis and after a glutenfree diet. Role of hfe in iron metabolism, hereditary haemochromatosis. Tfr2hfe complex is required for transcriptional regulation of hepcidin by holotf. Hfe heredi tary hemochromatosis protein mutated in type i hh 69. Abstract our understanding of the mechanisms by which the body regulates iron absorption and iron homeostasis has improved greatly in recent years with the identification of key molecules such as hfe, ferroportin, transferrin receptor 2, hepcidin and hemojuvelin. Role of the hypoxia inducible factors hif in iron metabolism.
The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. The relationship of h63d hfe gene mutations with chronic hepatitis c and the possible influence of hcv infection on iron metabolism needs further analysis. In the liver, hfe has been localized to hepatocytes 21, 39, kupffer cells 3, sinusoidal lining cells, and bile duct epithelial cells. Hfe gene mutations c282y and h63d are responsible for the majority of. Association with the c282y and h63d variants in hfe the possibility that variants related to iron metabolism and genetic. Hfe gene mutations and iron metabolism in wilsons disease. Hfe genotype in patients with hemochromatosis and other. Viral infections that disrupt liver function can be. The hemochromatosis protein hfe inhibits iron export from. Hcv infection seems to be a negative predictive marker of hfe gene mutations in patients with iron overload. Iron absorption and hepcidin regulation in the recent years a major progress in the understanding of iron metabolism has been made. Iron metabolism must be tightly controlled in order to avoid deleterious situations, including iron overload diseases, especially hferelated hemochromatosis. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. Hereditary hemochromatosis hhc due to mutations in the hfe gene is an autosomal recessive disorder of iron metabolism.
Iron metabolism must be tightly controlled in order to avoid deleterious situations, including iron overload diseases, especially hfe related hemochromatosis. Table 1 lists the genes currently known to have a role in the absorption of dietary iron and the maintenance of cellular iron homeostasis. One of the bettercharacterized genes responsible for hereditary haemochromatosis is hfe on chromosome 6, which codes for a protein that participates in the regulation of iron absorption. We propose a molecular model in which hfe has two mutually exclusive activities in cells. Hepcidin, a key regulator of iron metabolism and mediator. It highlights the effects of gene variants of hfe h63d and c282yhfe on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases. Although the importance of hfe in iron regulation is apparent in hh patients and mouse models levy et al. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly interconnected.
However, information with respect to the function of hfe protein does not explain how mutations in hfe lead to hereditary haemochromatosis. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. The hfe gene provides instructions for producing a protein that is located on the surface of cells, primarily liver and intestinal cells. Hereditary hemochromatosis hh is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and progressive storage resulting in organ damage.
Hereditary hemochromatosis hh is a disorder of iron metabolism caused by common mutations in the gene hfe. Hereditary hemochromatosis hh is an autosomal recessive disorder of iron metabolism with a carrier frequency of approximately 1 in 10 individuals of northern european ancestry. An overview of molecular basis of iron metabolism regulation and the associated pathologies. The hfe protein interacts with other proteins on the cell surface to detect the amount of iron in the body. Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation. Serum hepcidin level and human factors engineering hfe. Experimental hemochromatosis due to mhc class i hfe. The hfe protein binds to transferrin receptor1 tfr1 in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. Iron metabolism, volume 110, the latest release in the vitamins and hormones series first published in 1943, covers the field of hormone action, vitamin action, xray crystal structure, physiology and enzyme mechanisms, with this release focusing on topics relating to hepcidin, bacterial infection, and iron overload, the role of heparan. The disease is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues.
Bone morphogenetic proteinsmad signaling provides a key pathway of hepcidin activation, whereas the. Nov 26, 2002 hereditary hemochromatosis hh is a disorder of iron metabolism caused by common mutations in the gene hfe. To determine how hfe genotyping for the c282y and h63d mutations contributes to the diagnosis of hemochromatosis and to determine the prevalence of hfe mutations in a group of. The hfe protein is also found on some immune system cells. Iron as a therapeutic target in hferelated hemochromatosis. Since the tfr1 binding sites for hfe and fe2tf overlap, and as the tfr1. Pdf iron is an essential nutrient with limited bioavailability. Haemochromatosis is now known to be an iron storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin.
The role of hfe in transferrinbound iron uptake by hepatocytes anitac. An overview of molecular basis of iron metabolism regulation and. Pdf 5 citation of this article corresponding author of this article. Our current knowledge of iron metabolism and related disorders. C282y has reduced presence on membrane andor lack of interaction with tfr1, loss of inhibition of. The role of hfe in transferrinbound iron uptake by. Interaction of the hereditary hemochromatosis protein hfe with. Serum ferritin levels are increased in pcos, especially when glucose tolerance is abnormal, suggesting mild iron overload. Viral infections that disrupt liver function can be accompanied by changes in iron. Iron metabolism as a target for the anemia of chronic kidney disease. Importance of iron within the body, iron exist in two oxidation states. Haemochromatosis oxford academic journals oxford university. Hereditary hemochromatosis is a common inherited disorder of iron metabolism. Age, serum markers of iron metabolism, total lymphocyte counts, andhfeomim 235200 genotype are shown for each subject.
It highlights the effects of gene variants of hfe h63d and c282y hfe on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases. They found significant association of snps at the tf gene as well as at the hfe gene with iron deficiency. Hfe genotype in patients with hemochromatosis and other liver. Recent concepts in iron metabolism and hfe mutations powell. In an analysis of several genes modulating iron status, pelucchi et al. Pdf iron metabolism has been intensively examined over the last. May 11, 2012 the polycystic ovary syndrome pcos is associated with insulin resistance and abnormal glucose tolerance. Intestinal absorption of iron in hfe1 hemochromatosis journal of. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. The normal iron circuit includes the uptake of iron from transferrin by developing erythroblasts, the incorporation of iron into heme, red blood cell rbc production, rbc survival, and rbc senescence in the spleen with return of iron to the bone marrow via transferrin.
Physiologic systemic iron metabolism in mice deficient for duodenal hfe. Jun 14, 20 therefore, the present study aimed to 1 evaluate the role of the liver in regulating iron metabolism, based on the long. In such conditions an iron depletive treatment is engaged in order to avoid the development of complications. It is an autosomal recessive disorder in iron metabolism that is characterized by excess iron absorption, saturation of ironbinding proteins and. Ghalso named hfe1 haemochromatosisis an iron overload autosomal recessive disease. Olynyk,1,2 anddebbietrinder1,2 hferelated hereditary hemochromatosis results in hepatic iron overload. Also, in epithelial cells of the crypts of the duodenum, the hfetfr complex modulates the ironabsorbing function that the cell will have after migration to the tip of the villus. Pdf a revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. Haemochromatosis is now known to be an ironstorage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin.
Iron is essential for fundamental metabolic processes in. Hfe gene mutations in polish patients with disturbances of. Hfe hereditary hemochromatosis protein mutated in type i hh 69. Iron overload can cause hepatic cirrhosis, hepatocellular carcinoma, diabetes. Hereditary hemochromatosis hh is a common inherited disorder of iron metabolism that affects between 1 in 200 and 1 in 400 persons of northern european descent and is characterized by increased gastrointestinal iron absorption with subsequent tissue iron deposition. Normal hfe complexes with tfr1 reducing iron transfer into cells. Hfehaemochromatosis is rare and acquired iron overload is common, careful. The molecular biology of human iron metabolism oxford academic. Pdf on may 1, 2000, pa andrews and others published disorders of iron metabolism.
Localization of iron metabolismrelated mrnas in rat liver. The regulation of dietary iron absorption is complex and understanding is incomplete. Hereditary hemochromatosis, a primary inherited disorder of iron metabolism. Under iron homeostatic conditions, hfe is partially localized at the hepatocyte. Hereditary haemochromatosis is an iron overloading disorder caused by common mutations in the hfe gene. Pdf hemochromatosis gene mutations and iron metabolism. Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. However, expression in the liver is high relative to other tissues. Therefore, the present study aimed to 1 evaluate the role of the liver in regulating iron metabolism, based on the long.
May 12, 2014 they found significant association of snps at the tf gene as well as at the hfe gene with iron deficiency. In addition to regulating iron efflux from kupffer cells, hfe could act in the sensing of the iron status of the body or regulation of iron homeostasis in hepatocytes. The discovery of hepcidin and its role in iron metabolism could lead to new. Cells are able to regulate themselves the expression of the iron metabolism related genes through different posttranscriptional mechanisms, such as the alternative splicing, micrornas, the irpire system and the proteolytic cleavage. A homozygous mutation of hfe gene h63d is an indication of an iron metabolism disorder known as hemochromatosis iron overload and may increase the risk to develop a fatty liver, cryptic nonspecific liver dysfunctions, metabolic syndrome and, in patients with a cirrhotic or a liver damaged due to alcohol also the rates of liver cancer. In recent years, the interactions between viruses and cellular metabolism have become a topic of great interest. Diseasecausing mutations in hfe result in decreased hepcidin production both in hh patients and in hfe mice when. In anemia of inflammation, hepcidin production is increased up to 100fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. Identification of hfe, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as tfr2, that are important in non hfe associated iron overload. Factors contributing to potential iron overload in pcos include the iron sparing effect of chronic.
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