铁代谢红细胞系调节因子与铁稳态

红细胞合成是人类和其他脊椎动物最耗铁的生理过程,对机体铁稳态具有重要调节作用。Erythroferrone（ERFE）是红细胞系来源的调节铁调素的主要激素。当机体存在应激性红细胞合成时,ERFE合成增加,铁调素表达受抑,可促进机体铁吸收和储铁动员,满足红细胞合成对铁的需求,但在无效红细胞生成疾病中,通过此作用也导致了铁过载的发生。ERFE抑制肝细胞合成铁调素的作用机制尚不清楚,但至少部分地依赖BMP/SMAD信号通路。ERFE对铁代谢障碍性疾病和红细胞生成紊乱性贫血有重要的诊断及治疗价值。     

Iron homeostasis: insights from genetics and animal models

Disorders that perturb iron balance are among the most prevalent human diseases, but until recently iron transport remained poorly understood. Over the past five years, genetic studies of patients with inherited iron homeostasis disorders and the analysis of mutant mice, rats and zebrafish have helped to identify several important iron-transport proteins. With information being mined from the genomes of four species, the study of iron metabolism has benefited enormously from positional-cloning efforts. Complementing the genomic strategy, targeted mutagenesis in mice has produced new models of human iron diseases. The animal models described in this review offer valuable tools for investigating iron homeostasis in vivo.     

Iron Imports. V. Transport of iron through the intestinal epithelium

Iron absorption across the brush-border membrane requires divalent metal transporter 1 (DMT1), whereas ferroportin (FPN) and hephaestin are required for exit across the basolateral membrane. However, how iron passes across the enterocyte is poorly understood. Both chaperones and transcytosis have been postulated to account for intracellular iron transport. With iron feeding, DMT1 undergoes endocytosis and FPN translocates from the apical cytosol to the basolateral membrane. The fluorescent metallosensor calcein offered to the basolateral surface of enterocytes is found in endosomes in the apical compartment, and its fluorescence is quenched when iron is offered to the apical surface. These experiments are consistent with vesicular iron transport as a possible pathway for intracellular iron transport.     

Foot-shock Stress-Induced Regional Iron Accumulation and Altered Iron Homeostatic Mechanisms in Rat Brain

Like in other organs, iron in the brain plays an important role in various biological processes. Previous studies have shown that systemic iron homeostasis in mammalians was changed under specific stress conditions. The present study aimed to investigate effects of stress on brain iron homeostasis in rats using a foot-shock stress model. Young adult male Sprague-Dawley rats were randomly assigned to foot-shock stress group subjected to 30 min of cutaneous foot-shock (0.80 mA, 1 pulse/s, 300 ms duration) daily for 1 week or control group left undisturbed. Then, the rats were sacrificed and iron concentration in serum, liver, and some brain regions were measured using atomic absorption spectrophotometry. Expression of ferritin, Transferrin receptor (TfR), divalent metal transporter 1 (DMT1, with or without iron-responsive element), lactoferrin (Lf), and iron regulatory protein 1 (IRP1) in rat hippocampus were determined using western blot analysis. The results showed that stress induced decreased serum iron concentration, increased liver iron content, and elevated iron contents in specific brain regions including hippocampus, striatum, and frontal cortex. In the hippocampus, stress caused decreased expression of ferritin, increased expression of TfR and IRP1, and no change in expression of DMT1 or Lf. Results of this study demonstrated that foot-shock stress induced region specific iron accumulation and altered iron homeostatic mechanisms in the brain in addition to a changed systemic iron homeostasis characterized by decreased serum iron concentration and increased liver iron content. And, elevated IRP1 expression might be associated with the increased TfR and decreased ferritin expression, leading to subsequent iron accumulation and possible increased vulnerability to oxidative damage in hippocampus.     

Iron and copper homeostasis and intestinal absorption using the Caco2 cell model

Whole body homeostasis can be viewed as the balance between absorption and excretion, which can be regulated independently. Present evidence suggests that for iron, intestinal absorption is the main site for homeostatic regulation, while for copper it is biliary excretion. There are connections between iron and copper in intestinal absorption and transport. The blue copper plasma protein, ceruloplasmin, and its intracellular homologue, hephaestin, play a role in cellular iron release. The studies reviewed here compare effects of Fe(II) and Cu(II) on their uptake and overall transport by monolayers of polarized Caco2 cells, which model intestinal mucosa. In the physiological range of concentrations, depletion of cellular iron or copper (by half) increased uptake of both metal ions. Depletion of iron or copper also enhanced overall transport of iron from the apical to the basal chamber. Copper depletion enhanced overall copper transport, but iron depletion did not. Pretreatment with excess copper also stimulated copper absorption. Plasma ceruloplasmin (added to the basal chamber) failed to enhance basolateral iron release, and Zn(II) failed to compete with Cu(II) for uptake. Neither copper nor iron deficiency altered expression of IREG1 or DMT1 (-IRE form) at the mRNA level. Thus, in the low-normal range of iron and copper availability, intestinal absorption of both metals appears to be positively related to the need for these elements by the whole organism. The two metal ions also influenced each other's transport; but with copper excess, other mechanisms come into play.     

Iron transport and the kidney

Over the last decade there has been an explosion in our understanding of the proteins that modulate iron homeostasis. Much research has focused on the tissues classically associated with iron absorption and metabolism, namely the duodenum, the liver and the reticulo-endothelial system. Expression profiling has highlighted that many of the components associated with iron homeostasis, are also expressed in tissues which hitherto have received relatively little attention in terms of iron research. These include, testis, lung and, the subject of this review, the kidney. The latter is of great interest because other than a source of erythropoietin, a function that is of course of utmost importance for iron homeostasis, the kidney is regarded as more or less irrelevant in terms of iron handling. However, the fact that the kidneys of our favourite subjects, namely rats, mice and humans, contain many if not all of the proteins that are central to iron balance, that in some cases are expressed in considerable amounts, implies that the kidney handles iron in some way that has demanded evolutionary conservation and therefore is likely to be of importance.     

Non-heme Iron as Ferrous Sulfate Does Not Interact with Heme Iron Absorption in Humans

The absorption of heme iron has been described as distinctly different from that of non-heme iron. Moreover, whether heme and non-heme iron compete for absorption has not been well established. Our objective was to investigate the potential competition between heme and non-heme iron as ferrous sulfate for absorption, when both iron forms are ingested on an empty stomach. Twenty-six healthy nonpregnant women were selected to participate in two iron absorption studies using iron radioactive tracers. We obtained the dose?Cresponse curve for absorption of 0.5, 10, 20, and 50?mg heme iron doses, as concentrated red blood cells. Then, we evaluated the absorption of the same doses, but additionally we added non-heme iron, as ferrous sulfate, at constant heme/non-heme iron molar ratio (1:1). Finally, we compare the two curves by a two-way ANOVA. Iron sources were administered on an empty stomach. One factor analysis showed that heme iron absorption was diminished just by increasing total heme iron (P?<?0.0001). The addition of non-heme iron as ferrous sulfate did not have any effect on heme iron absorption (P?=?NS). We reported evidence that heme and non-heme iron as ferrous sulfate does not compete for absorption. The mechanism behind the absorption of these iron sources is not clear.     

The cellular mechanisms of body iron homeostasis

Cells tightly regulate iron levels through the activity of iron regulatory proteins (IRPs) that bind to RNA motifs called iron responsive elements (IREs). When cells become iron-depleted, IRPs bind to IREs present in the mRNAs of ferritin and the transferrin receptor, resulting in diminished translation of the ferritin mRNA and increased translation of the transferrin receptor mRNA. Similarly, body iron homeostasis is maintained through the control of intestinal iron absorption. Intestinal epithelia cells sense body iron through the basolateral endocytosis of plasma transferrin. Transferrin endocytosis results in enterocytes whose iron content will depend on the iron saturation of plasma transferrin. Cell iron levels, in turn, inversely correlate with intestinal iron absorption. In this study, we examined the relationship between the regulation of intestinal iron absorption and the regulation of intracellular iron levels by Caco-2 cells. We asserted that IRP activity closely correlates with apical iron uptake and transepithelial iron transport. Moreover, overexpression of IRE resulted in a very low labile or reactive iron pool and increased apical to basolateral iron flux. These results show that iron absorption is primarily regulated by the size of the labile iron pool, which in turn is regulated by the IRE/IRP system.     

小肠铁释放机制及相关疾病研究进展

铁是生物体必需的微量元素。铁缺乏和铁过载均会导致铁代谢紊乱相关疾病,因此有关机体铁水平稳态的调节机制已成为了目前铁代谢领域的研究热点。小肠吸收细胞是调节肠铁吸收、肠铁释放,以及维持机体铁稳态的重要部位。最新的研究表明,铁从小肠吸收细胞基底端释放入血液循环,主要是由膜铁转运蛋白（ferroportin1,Fp1）介导,并在膜铁转运辅助蛋白（haphaestin,Hp）和铜蓝蛋白（ceruloplasmin,Cp）的参与下完成。其中Fp1在小肠铁释放过程中起着至关重要的作用。本文重点阐述铁释放相关蛋白Fp1的作用机制及其调节机制,并详细介绍Fp1基因突变导致的铁代谢相关疾病方面的最新研究讲展。     

Intestinal iron absorption

Intestinal iron absorption is a critical process for maintaining body iron levels within the optimal physiological range. Iron in the diet is found in a wide variety of forms, but the absorption of non-heme iron is best understood. Most of this iron is moved across the enterocyte brush border membrane by the iron transporter divalent metal-ion transporter 1, a process enhanced by the prior reduction of the iron by duodenal cytochrome B and possibly other reductases. Enterocyte iron is exported to the blood via ferroportin 1 on the basolateral membrane. This transporter acts in partnership with the ferroxidase hephaestin that oxidizes exported ferrous iron to facilitate its binding to plasma transferrin. Iron absorption is controlled by a complex network of systemic and local influences. The liver-derived peptide hepcidin binds to ferroportin, leading to its internalization and a reduction in absorption. Hepcidin expression in turn responds to body iron demands and the BMP-SMAD signaling pathway plays a key role in this process. The levels of iron and oxygen in the enterocyte also exert important influences on iron absorption. Disturbances in the regulation of iron absorption are responsible for both iron loading and iron deficiency disorders in humans.     

Iron transport kinetics through blood-brain barrier endothelial cells

Background

Transferrin and its receptors play an important role during the uptake and transcytosis of iron through blood-brain barrier (BBB) endothelial cells (ECs) to maintain iron homeostasis in BBB endothelium and brain. Any disruptions in the cell environment may change the distribution of transferrin receptors on the cell surface, which eventually alter the homeostasis and initiate neurodegenerative disorders. In this paper, we developed a comprehensive mathematical model that considers the necessary kinetics for holo-transferrin internalization and acidification, apo-transferrin recycling, and exocytosis of free iron and transferrin-bound iron through basolateral side of BBB ECs.

Iron mobilization using chelation and phlebotomy

Knowledge of the basic mechanisms involved in iron metabolism has increased greatly in recent years, improving our ability to deal with the huge global public health problems of iron deficiency and overload. Several million people worldwide suffer iron overload with serious clinical implications. Iron overload has many different causes, both genetic and environmental. The two most common iron overload disorders are hereditary haemochromatosis and transfusional siderosis, which occurs in thalassaemias and other refractory anaemias. The two most important treatment options for iron overload are phlebotomy and chelation. Phlebotomy is the initial treatment of choice in haemochromatosis, while chelation is a mainstay in the treatment of transfusional siderosis. The classical iron chelator is deferoxamine (Desferal), but due to poor gastrointestinal absorption it has to be administered intravenously or subcutaneously, mostly on a daily basis. Thus, there is an obvious need to find and develop new effective iron chelators for oral use. In later years, particularly two such oral iron chelators have shown promise and have been approved for clinical use, namely deferiprone (Ferriprox) and deferasirox (Exjade). Combined subcutaneous (deferoxamine) and oral (deferiprone) treatment seems to hold particular promise.     

Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung

Ferroportin 1 (FPN1; aka MTP1, IREG1, and SLC40A1), which was originally identified as a basolateral iron transporter crucial for nutritional iron absorption in the intestine, is expressed in airway epithelia and upregulated when these cells are exposed to iron. Using immunofluorescence labeling and confocal microscopic imaging techniques, we demonstrate that in human and rodent lungs, FPN1 localizes subcellularly to the apical but not basolateral membrane of the airway epithelial cells. The role of airway epithelial cells in iron mobilization in the lung was studied in an in vitro model of the polarized airway epithelium. Normal human bronchial epithelial cells, grown on membrane supports until differentiated, were exposed to iron, and the efficiency and direction of iron transportation were studied. We found that these cells can efficiently take up iron across the apical but not basolateral surface in a concentration-dependent manner. Most of the iron taken up by the cells is then released into the medium within 8 h in the form of less reactive protein-bound complexes including ferritin and transferrin. Interestingly, iron release also occurred across the apical but not basolateral membrane. Our findings indicate that FPN1, depending on its subcellular location, could have distinct functions in iron homeostasis in different cells and tissues. Although it is responsible for exporting nutrient iron from enterocytes to the circulation in the intestine, it could play a role in iron detoxification in airway epithelial cells in the lung.     

Iron homeostasis: recently identified proteins provide insight into novel control mechanisms

Iron is an essential nutrient required for a variety of biochemical processes. It is a vital component of the heme in hemoglobin, myoglobin, and cytochromes and is also an essential cofactor for non-heme enzymes such as ribonucleotide reductase, the limiting enzyme for DNA synthesis. When in excess, iron is toxic because it generates superoxide anions and hydroxyl radicals that react readily with biological molecules, including proteins, lipids, and DNA. As a result, humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Disruption of these processes causes either iron-deficient anemia or iron overload disorders. In this minireview, we focus on the roles of recently identified proteins in the regulation of iron homeostasis.     

Iron Imports. VI. HFE and regulation of intestinal iron absorption

The majority of clinical cases of iron overload is caused by mutations in the HFE gene. However, the role that HFE plays in the physiology of intestinal iron absorption remains enigmatic. Two major models have been proposed: 1) HFE exerts its effects on iron homeostasis indirectly, by modulating the expression of hepcidin; and 2) HFE exerts its effects directly, by changing the iron status (and therefore the iron absorptive activity) of intestinal enterocytes. The first model places the primary role of HFE in the liver (hepatocytes and/or Kupffer cells). The second model places the primary role in the duodenum (crypt cells or villus enterocytes). These models are not mutually exclusive, and it is possible that HFE influences the iron status in each of these cell populations, leading to cell type-specific downstream effects on intestinal iron absorption and body iron distribution.     

Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities

Iron is a key micronutrient for the human body and participates in biological processes, such as oxygen transport, storage, and utilization. Iron homeostasis plays a crucial role in the function of the heart and both iron deficiency and iron overload are harmful to the heart, which is partly mediated by increased oxidative stress. Iron enters the cardiomyocyte through the classic pathway, by binding to the transferrin 1 receptor (TfR1), but also through other routes: T-type calcium channel (TTCC), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), Zrt-, Irt-like Proteins (ZIP) 8 and 14. Only one protein, ferroportin (FPN), extrudes iron from cardiomyocytes. Intracellular iron is utilized, stored bound to cytoplasmic ferritin or imported by mitochondria. This cardiomyocyte iron homeostasis is controlled by iron regulatory proteins (IRP). When the cellular iron level is low, expression of IRPs increases and they reduce expression of FPN, inhibiting iron efflux, reduce ferritin expression, inhibiting iron storage and augment expression of TfR1, increasing cellular iron availability. Such cellular iron homeostasis explains why the heart is very susceptible to iron overload: while cardiomyocytes possess redundant iron importing mechanisms, they are equipped with only one iron exporting protein, ferroportin. Furthermore, abnormalities of iron homeostasis have been found in heart failure and coronary artery disease, however, no clear picture is emerging yet in this area. If we better understand iron homeostasis in the cardiomyocyte, we may be able to develop better therapies for a variety of heart diseases to which abnormalities of iron homeostasis may contribute.     

Iron and mechanisms of emotional behavior

Iron is required for appropriate behavioral organization. Iron deficiency results in poor brain myelination and impaired monoamine metabolism. Glutamate and γ-aminobutyric acid homeostasis is modified by changes in brain iron status. Such changes produce not only deficits in memory/learning capacity and motor skills, but also emotional and psychological problems. An accumulating body of evidence indicates that both energy metabolism and neurotransmitter homeostasis influence emotional behavior, and both functions are influenced by brain iron status. Like other neurobehavioral aspects, the influence of iron metabolism on mechanisms of emotional behavior is multifactorial: brain region-specific control of behavior, regulation of neurotransmitters and associated proteins, temporal and regional differences in iron requirements, oxidative stress responses to excess iron, sex differences in metabolism, and interactions between iron and other metals. To better understand the role that brain iron plays in emotional behavior and mental health, this review discusses the pathologies associated with anxiety and other emotional disorders with respect to body iron status.