骨形态发生蛋白6对机体铁代谢调控的机制

骨形态发生蛋白6(BMP6)为TGF-β超家族中的一员,已有的研究表明BMP6具有成骨和成软骨作用,最新的研究发现了它对机体的铁代谢也具有重要的调控作用,通过调节铁调素(hepcidin)的表达,在调节机体铁稳态过程中扮演着重要角色。     

铁代谢与蛋白质泛素化．降解调控研究进展

铁元素为几乎所有的生命体所必需,维持铁代谢稳态对机体的正常功能至关重要。铁代谢紊乱与人类多种疾病的发生和发展有关。已知铁代谢稳态受到一系列参与铁代谢环节的关键蛋白质,如IRP2等的精确调节。这些重要蛋白质的稳定性、生理活性的动态变化及其协调作用是细胞维持铁代谢平衡的分子基础。除了转录和转录后水平的调控,泛素化等翻译后修饰方式和蛋白质降解是细胞精确调控参与铁代谢的蛋白质的水平及功能普遍而有效的方式之一;同时,细胞的铁代谢状态也影响细胞内参与泛素化等翻译后修饰途径的酶类的活性和稳定性,从而在铁代谢和蛋白质修饰．降解途径之间形成反馈机制,实时和动态地完成对细胞内铁代谢水平的精确调控。就相关领域的最新进展作简要综述。     

铁代谢与铁调素hepcidin

铁是机体必需的营养元素。然而,铁过载则导致细胞的损伤。由于生物体缺少排泄铁的机制,因而,肠铁吸收的调控便成为维持机体铁稳态的关键。新近研究发现hepcidin对机体铁稳态的调节起着至关重要的作用,被人们称为铁调节激素。Hepcidin主要在肝细胞中合成,之后分泌至血液将体内铁需要的信号传至小肠,调控肠铁的吸收。这一过程主要通过调节小肠铁转运相关蛋白的表达而实现。任何影响hepcidin表达的因素都可能破坏体内的铁平衡,造成铁代谢相关疾病。     

铜蓝蛋白与脑铁代谢

铜蓝蛋白（Cerulopasmin,CP)是人体重要的亚铁氧化酶。它的主要作用是催化二阶铁成为三阶铁,从而促进铁与转铁蛋白结合。由于它的     

铁代谢调节分子Erythroferrone研究进展

红细胞来源的erythroferrone (ERFE)是最近发现的一种重要的铁代谢调节蛋白。在应激红细胞生成过程中,促红细胞生成素（EPO）能够促使骨髓有核红细胞分泌ERFE,从而抑制肝脏铁调素合成,进而稳定铁释放蛋白（FPN1）的水平,最终增加铁的吸收和动员。铁是红细胞生成不可缺少的重要原料之一,当红细胞生成增加时,需要充足的铁来合成血红素和血红蛋白。血液中的ERFE在红细胞生成时为保障稳定的铁供应发挥着重要作用。本文就ERFE的发现、基因结构和蛋白质结构、分布,ERFE在糖脂代谢、红细胞生成和铁代谢中的作用,以及ERFE功能异常与β-地中海贫血和慢性肾脏疾病等疾病的联系,ERFE在基础研究与临床检测中的应用,尤其是EPO/ERFE/hepcidin-FPN1在铁代谢调控中的作用机制展开论述,以期为靶向治疗铁代谢失衡疾病提供参考。     

脑内的铁,转铁蛋白及转铁蛋白受体

脑铁异常增高可能参与脑神经变性疾病的发生发展。这一发现使得脑铁代谢成为近年广为关注和研究较为广泛的领域。本文综述了这一领域某些方面的目前认识。包括：（１）脑铁分布及功能;（２）铁转铁蛋白及转铁蛋白受体在脑内的合成与分布;（３）脑铁摄取和运输。此外,对铁与某些金属离子,转的蛋白和转铁蛋白受体与脑神经变性疾病的关系,以及转铁蛋白受体内吞在生物大分子跨血脑屏障运输中的作用也作了简要讨论。     

脑铁代谢和神经变性性疾病

最近关于脑铁代谢研究的新成果,尤其是与脑铁转运、储存、调节相关的某些突变基因的发现,足以得出以下结论,即异常增高的脑铁至少是部份神经变性疾病的起始原因。研究显示,脑铁过量积聚主要是由于遗传性和非遗传性因素所引起的某些服铁代谢蛋白功能异常或表达失控。正是异常增高的脑铁触发一系列病理反应,最终导致神经为性性疾病病人服神经元死亡。本文简要叙述了目前对服铁分布、功能和脑铁代谢蛋白的认识,讨论了内铁转运机制以及服铁和神经变性性疾病之间的关系研究的新进展。     

Hepcidin非铁调控因子研究进展

铁调素（Hepcidin）是由肝细胞分泌的维持人体系统性铁平衡的核心因子,其通过改变细胞膜铁转运蛋白（ferroportin,Fpn）的表达量以调控肠黏膜细胞和巨噬细胞内铁的转出水平,从而决定机体循环铁水平并影响肝脏等主要储铁脏器的铁负荷程度。根据近年来的研究发现,影响Hepcidin表达的主要因素可以归纳为两个方面：一是机体本身对铁的需求,而由于铁本身又是Hb（hemoglobin,血红蛋白）的合成原料以及携氧成份,因此还应包括机体对Hb合成和缺氧的反应,介导因子主要包括携铁转铁蛋白（holo—transferrin,holo—Tf）、促红细胞生成素（erythropoietin,EPO）和缺氧诱导因子-1（hypoxia．inducible factor1,HIF．1）;另一则是源于疾病病理过程中相关致病因素、细胞因子、激素等非铁调控因子的改变对其表达调控机制产生的影响,并通过扰乱机体铁稳态加速疾病的发展或加重病情。随着研究资料的积累,糖尿病、部分心血管疾病、酒精性或非酒精性脂肪肝等慢性疾病存在铁过负荷已是不争的事实,多种hepcidin非铁调控因子在代谢紊乱型铁过负荷综合征（sysmetabolic iron overload syndrome）发生过程中的作用受到了广泛重视。对一些常见疾病中引起hepcidin表达变化异常和铁代谢紊乱的非铁因子及其作用机制的研究进展进行综述。     

单核巨噬细胞铁代谢相关蛋白的表达调控

人类机体的铁代谢表现为受限制的对外界铁的吸收和有效的机体内的铁的再循环利用,单核巨噬细胞系统通过吞噬衰老的红细胞,储存和释放铁,在机体铁的循环再利用方面起到了重要的作用。因此,单核巨噬细胞系统对整个机体铁稳态的维持非常重要。近年来,随着转铁蛋白受体1(transferrin receptor1,TfR1)、铁蛋白(ferritin,Fn)、二价金属离子转运蛋白1(divalent metal transporter1,DMT1)、膜铁转运蛋白1(ferroportin1,FPN1),以及铁调素(hepcidin)等在单核巨噬细胞系统中功能和调控机制研究的不断深入,日益加深了人们对单核巨噬细胞系统的铁代谢过程和调控机制的了解。该文综述了铁水平、NO以及炎症等因素对单核巨噬细胞系统TfR1、Fn、DMT1、FPN1、hepcidin等蛋白表达的调控及其机制研究的最新进展。     

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。     

海帕西啶铁调节和血色素沉着

血色素沉着是一种血浆铁沉积过多而导致的器官损伤性疾病,多种铁调节基因如HFE、HJV、HAMP和TfR2等的突变均可导致该病的发生,其中HAMP是最为重要的一种。HAMP基因编码一种名为海帕西啶的小肽,是小肠铁重吸收和巨噬细胞铁释放的负调节因子。海帕西啶含量的减少将导致血清铁过负荷和血色素沉着的发生,HFE、HJV和TfR2等基因可影响海帕西啶的表达,从而使海帕西啶成为血色素沉着的中央调节者。这些研究对血色素沉着发生机制的理解及其诊断和治疗具有重要意义。     

Parallels and contrasts between iron and copper metabolism

This paper reviews the Second International Workshop on Iron and Copper Homeostasis, held in Pucón, Chile 10–13 November, 2001. We cover the presentations and papers published (this issue) with the intent to point out parallels, contrasts and cutting edge areas rather than to say something about every paper. Iron and copper metabolism have been intertwined for nearly 150 years and the interrelationship is growing with advances in understanding the role of ceruloplasmin as one example and the probable role of hephaestin as another. The transporter DMT1 (divalent metal transporter 1) clearly plays a major part in iron uptake and trafficking. Emerging evidence suggests that it plays a lesser role in manganese, cadmium and copper transport; but it is still being evaluated there. Yet another interaction may come from the IRE/IRP (Iron Responsive Element/Iron Regulatory Protein) story where a paradigmatic role in iron homeostasis is well established, but interaction with copper is only now emerging. Parallels include the nutrient status of both metals based on their utility for redox reactions as well as their toxicity primarily via reactive oxygen species. The workshop also revealed that alternate splicing of pre-mRNAs for iron and copper related proteins and tissue specific responses are additional similarities. Regulation of gene expression and excretion offered contrasts between the two metals. The workshop also considered a series of continuing and emerging issues.     

Generation of conditional alleles of the murine Iron Regulatory Protein (IRP)-1 and -2 genes

Central aspects of cellular iron metabolism are controlled by IRP1 and IRP2, which are ubiquitously expressed in mouse organs and cells. Total and constitutive deficiency of both IRPs causes embryonic lethality in the mouse. To bypass the early lethality and to study organ-specific and/or temporal functions of IRP1 and/or IRP2 we generated Irp1 and Irp2 conditional alleles. We used mouse lines where a betaGeo gene trap construct was inserted into the second intron of the Irp1 and the Irp2 gene, generating hypomorphic alleles by interrupting the corresponding open reading frame near the amino-termini. The gene trap cassettes are flanked by Frt sites and were co-inserted with LoxP sites flanking exon 3. Flp-mediated removal of the gene trap construct generates floxed alleles with wildtype functions. For both Irp genes, Cre-assisted deletion of exon 3 generates complete null alleles that, in the case of IRP2, are associated with altered body iron distribution and compromised hematopoiesis. If not removed, the gene trap construct causes partially penetrant embryonic lethality unrelated to IRP deficiency when inserted within the Irp1 but not the Irp2 locus. We discuss the implications for functional genomics in the mouse.     

Hemojuvelin在铁稳态平衡中的关键作用

铁调素（hepcidin）是由肝脏分泌的一种肽类激素,它通过改变细胞膜上ferroportin的水平而调节全身铁代谢。Ferroportin是唯一已知的哺乳动物中的铁外排通道,它表达在小肠细胞的基底外侧膜和巨噬细胞的质膜上。铁调素结合ferroportin导致其在溶酶体内降解,从而减少铁从饮食的吸收和巨噬细胞铁的释放。Hemojuvelin（HJV）是一种glycosylphosphatidylinositol（GPI）相连的膜蛋白,它作为骨形态发生蛋白（BMP）的共受体可以激活肝细胞Smad信号通路和铁调素表达。除了表达在细胞膜上,hemojuvelin还可以被切割并分泌到胞外,形成可溶性蛋白。由furin切割产生的可溶性HJV可以选择性地结合到BMP配体,抑制内源性BMP诱导的铁调素表达。TMPRSS6也被认为可以切割细胞膜上HJV并影响铁调素的表达。最近的研究表明,HJV还可能参与脂肪组织对铁代谢的调控。综述了近期对细胞膜HJV和可溶性HJV如何调节铁调素的表达与铁代谢的研究结果,并对这一研究领域需要填补的空白进行了初步探讨。     

Brain iron transport

Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.     

Hepcidin: regulation of the master iron regulator

Iron, an essential nutrient, is required for many diverse biological processes. The absence of a defined pathway to excrete excess iron makes it essential for the body to regulate the amount of iron absorbed; a deficiency could lead to iron deficiency and an excess to iron overload and associated disorders such as anaemia and haemochromatosis respectively. This regulation is mediated by the iron-regulatory hormone hepcidin. Hepcidin binds to the only known iron export protein, ferroportin (FPN), inducing its internalization and degradation, thus limiting the amount of iron released into the blood. The major factors that are implicated in hepcidin regulation include iron stores, hypoxia, inflammation and erythropoiesis. The present review summarizes our present knowledge about the molecular mechanisms and signalling pathways contributing to hepcidin regulation by these factors.     

铁紊乱相关疾病的研究进展

铁作为一种必需的营养元素,在哺乳动物体内的重要作用越来越为人们所重视。动物体内存在着严格的铁代谢调节机制,以确保体内铁始终处于正常生理水平。如果铁代谢失调、体内铁缺乏或过负荷均会导致各种临床疾病。研究发现,肝脏抗菌多肽(hepcidin)很可能是一种控制小肠铁吸收及调节体内铁稳态的关键物质,是一种极为重要的铁调节激素。本文综述了铁的生理作用、铁缺乏引起的疾病(如:缺铁性贫血和儿童神经系统疾病)和铁过负荷引起的疾病(如:肝损伤、心血管疾病、帕金森病和癌症等),并对如何利用现代化技术手段在基因水平开展铁紊乱相关疾病的治疗做了展望。     

sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin

A sequence within the E2 domain of soluble amyloid precursor protein (sAPP) stimulates iron efflux. This activity has been attributed to a ferroxidase activity suggested for this motif. We demonstrate that the stimulation of efflux supported by this peptide and by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane of human brain microvascular endothelial cells (hBMVEC). The peptide does not bind ferric iron explaining why it does not and thermodynamically cannot promote ferrous iron autoxidation. This peptide specifically pulls Fpn down from the plasma membrane of hBMVEC; based on these results, FTP, for ferroportin‐targeting peptide, correctly identifies the function of this peptide. The data suggest that in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium. This inference correlates with the observation of significant iron deposition in the amyloid plaques characteristic of Alzheimer's disease.