scholarly journals Regulation of Iron Homeostasis and Related Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yikun Li ◽  
Xiali Huang ◽  
Jingjing Wang ◽  
Ruiling Huang ◽  
Dan Wan
Keyword(s):  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Gene Mutations ◽  
The Body ◽  
Hereditary Diseases ◽  
Iron Regulation ◽  
Iron Storage ◽  
Smad Pathway ◽  
Infection And Inflammation

The liver is the organ for iron storage and regulation; it senses circulating iron concentrations in the body through the BMP-SMAD pathway and regulates the iron intake from food and erythrocyte recovery into the bloodstream by secreting hepcidin. Under iron deficiency, hypoxia, and hemorrhage, the liver reduces the expression of hepcidin to ensure the erythropoiesis but increases the excretion of hepcidin during infection and inflammation to reduce the usage of iron by pathogens. Excessive iron causes system iron overload; it accumulates in never system and damages neurocyte leading to neurodegenerative diseases such as Parkinson’s syndrome. When some gene mutations affect the perception of iron and iron regulation ability in the liver, then they decrease the expression of hepcidin, causing hereditary diseases such as hereditary hemochromatosis. This review summarizes the source and utilization of iron in the body, the liver regulates systemic iron homeostasis by sensing the circulating iron concentration, and the expression of hepcidin regulated by various signaling pathways, thereby understanding the pathogenesis of iron-related diseases.

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

Abstract The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

scholarly journals The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value

2018 ◽  
Vol 11 (4) ◽  
pp. 115 ◽  
Author(s):  
Antonella Roetto ◽  
Mariarosa Mezzanotte ◽  
Rosa Pellegrino
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Iron Regulation ◽  
Role Taking ◽  
Therapeutic Value ◽  
Living Organisms ◽  
Type 3 ◽  
Functional Versatility ◽  
Transferrin Receptor 2

Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload. It has been recently pointed out that Hepc production and iron regulation could be exerted also in tissues other than liver, and that Tfr2 has an extrahepatic role in iron metabolism as well. This review summarizes all the most recent data on Tfr2 extrahepatic role, taking into account the putative distinct roles of the two main Tfr2 isoforms, Tfr2α and Tfr2β. Representing Hepc modulation an effective approach to correct iron balance impairment in common human diseases, and with Tfr2 being one of its regulators, it would be worthwhile to envisage Tfr2 as a therapeutic target.

scholarly journals Systems genetic analysis of multivariate response to iron deficiency in mice

2012 ◽  
Vol 302 (11) ◽  
pp. R1282-R1296 ◽  
Author(s):  
Lina Yin ◽  
Erica L. Unger ◽  
Leslie C. Jellen ◽  
Christopher J. Earley ◽  
Richard P. Allen ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Principal Components ◽  
Qtl Analysis ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Iron Regulation ◽  
Deficiency Anemia ◽  
Dietary Iron ◽  
Multiple Genes

The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strain-related variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.

The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2564-2570 ◽  
Author(s):  
Hanqian Carlson ◽  
An-Sheng Zhang ◽  
William H. Fleming ◽  
Caroline A. Enns
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Cell Types ◽  
Single Amino Acid ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Transferrin Receptor 1 ◽  
A Cell

AbstractHereditary hemochromatosis (HH) is an autosomal recessive disease that leads to parenchymal iron accumulation. The most common form of HH is caused by a single amino acid substitution in the HH protein, HFE, but the mechanism by which HFE regulates iron homeostasis is not known. In the absence of transferrin (Tf), HFE interacts with transferrin receptor 1 (TfR1) and the 2 proteins co-internalize, and in vitro studies have shown that HFE and Tf compete for TfR1 binding. Using a cell line lacking endogenous transferrin receptors (TRVb cells) transfected with different forms of HFE and TfR1, we demonstrate that even at low concentrations Tf competes effectively with HFE for binding to TfR1 on living cells. Transfection of TRVb cells or the derivative line TRVb1 (which stably expresses human TfR1) with HFE resulted in lower ferritin levels and decreased Fe2+ uptake. These data indicate that HFE can regulate intracellular iron storage independently of its interaction with TfR1. Earlier studies found that in HeLa cells, HFE expression lowers Tf-mediated iron uptake; here we show that HFE lowers non–Tf-bound iron in TRVb cells and add to a growing body of evidence that HFE may play different roles in different cell types.

Transferrin receptor 2 is emerging as a major player in the control of iron metabolism

2007 ◽  
Vol 2 (1) ◽  
pp. 34-55 ◽  
Author(s):  
Alessia Calzolari ◽  
Isabella Oliviero ◽  
Ugo Testa
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Cellular Localization ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Essential Element ◽  
Biological Properties ◽  
The Body ◽  
Major Player ◽  
Type 3

AbstractOur knowledge of mammalian iron metabolism has advanced dramatically over recent years. Iron is an essential element for virtually all living organisms. Its intestinal absorption and accurate cellular regulation is strictly required to ensure the coordinated synthesis of the numerous iron-containing proteins involved in key metabolic processes, while avoiding the uptake of excess iron that can lead to organ damage. A range of different proteins exist to ensure this fine control within the various tissues of the body. Among these proteins, transferrin receptor (TFR2) seems to play a key role in the regulation of iron homeostasis. Disabling mutations in TFR2 are responsible for type 3 hereditary hemochromatosis (Type 3 HH). This review describes the biological properties of this membrane receptor, with a particular emphasis paid to the structure, function and cellular localization. Although much information has been garnered on TFR2, further efforts are needed to elucidate its function in the context of the iron regulatory network.

Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice

2012 ◽  
Vol 302 (1) ◽  
pp. E77-E86 ◽  
Author(s):  
Soichiro Tajima ◽  
Yasumasa Ikeda ◽  
Kaori Sawada ◽  
Noriko Yamano ◽  
Yuya Horinouchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Inflammatory Cytokines ◽  
Iron Reduction ◽  
Iron Concentration ◽  
The Body ◽  
Macrophage Infiltration ◽  
Iron Storage ◽  
Kkay Mice

Iron is an essential trace metal for most organisms. However, excess iron causes oxidative stress through production of highly toxic hydroxyl radicals via the Fenton/Haber-Weiss reaction. Iron storage in the body is reported to be associated with fat accumulation and type 2 diabetes mellitus. We investigated the role of iron in adiposity by using KKAy mice and obese and diabetic model mice. Eight-week-old KKAy mice were divided into two groups and treated with deferoxamine (DFO), an iron chelator agent, or a vehicle for 2 wk. DFO treatment diminished fat iron concentration and serum ferritin levels in KKAy mice. Fat weight and adipocyte size were reduced significantly in DFO-treated mice compared with vehicle-treated mice. Macrophage infiltration into fat was also decreased in DFO-treated mice compared with vehicle-treated mice. Superoxide production and NADPH oxidase activity in fat, as well as urinary 8-hydroxy-2′-deoxyguanosine excretion, were decreased in KKAy mice after DFO treatment while p22phox expression in adipose tissue was diminished in such mice. Ferritin expression in the fat of DFO-treated KKAy mice was decreased. In addition, F4/80-positive cells also presented through both p22phox and ferritin expression. The mRNA expression levels of inflammatory cytokines were also reduced in fat tissue of DFO-treated mice. These findings suggest that reduction of iron levels ameliorates adipocyte hypertrophy via suppression of oxidative stress, inflammatory cytokines, and macrophage infiltration, thereby breaking a vicious cycle in obesity.

scholarly journals Peran Ferritin pada Stroke Iskemik Akut

2021 ◽  
Vol 10 (2) ◽  
pp. 127-132
Author(s):  
Lisda Amalia ◽  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Iron Homeostasis ◽  
Cell Damage ◽  
The Body ◽  
Neurological Deficits ◽  
Iron Storage ◽  
The Central Nervous System ◽  
Focal Injury ◽  
Iron Storage Protein

Stroke is a neurological deficit that occurs due to acute focal injury to the central nervous system that occurs solely due to vascular disorders, including cerebral infarction or bleeding. Ferritin is an intracellular and extracellular iron storage protein which is essential for iron homeostasis in the body. Ferritin is expressed in microglia and macrophages, and also in neurons. If there is cell damage due to ischemic stroke, ferritin will leave the cells and enter the serum. The hypoxia-ischemic state in stroke induces the expression of ferritin in oligodendrocytes and microglia. When there is oxidative stress, ferritin formation will increase. The function of ferritin in times of oxidative stress is still controversial. Ferritin in this condition can act as a scavenger and as a donor for free iron ions. Ischemic stroke patients with larger lesions and more severe neurological deficits showed higher serum ferritin levels and a higher likelihood of complications of bleeding transformation.

scholarly journals Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

2021 ◽  
Vol 22 (12) ◽  
pp. 6493
Author(s):  
Elizabeta Nemeth ◽  
Tomas Ganz
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Genetic Diseases ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Extracellular Fluid ◽  
Peptide Hormone ◽  
Cellular Iron ◽  
The Stability ◽  
Iron Delivery

Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

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