低氧诱导因子对铁代谢的调节（英文）

低氧诱导因子(hypoxia-inducible factors,HIFs)是一类介导细胞内低氧反应的核转录复合体。HIF-α和HIF-β形成有功能的异质二聚体。哺乳动物中有HIF-1α、HIF-2α和HIF-3α。HIFs在铁代谢中发挥重要作用。受HIFs调节的铁代谢相关蛋白主要有二价金属转运蛋白1(divalent metal transporter 1,DMT1)、铁转出蛋白(ferroportin 1,FPN1)、十二指肠铁细胞色素b(duodenal cytochrome b,Dcytb)和转铁蛋白受体(transferrin receptor,Tf R)。铁调素(hepcidin)和铁调节蛋白(iron regulatory proteins,IRPs)是调节机体与细胞内铁代谢、维持铁稳态的重要因子,同样受到HIFs的调节。本文综述了HIFs对上述铁代谢相关蛋白的调节作用,以期为治疗铁代谢相关疾病提供可能的靶点。     

缺氧信号转导通路的研究进展

人体组织和细胞在环境氧浓度改变的条件下,通过氧感受器和信号转导通路特异地调节某些基因或蛋白的表达来适应低氧.同时在缺氧情况下,缺氧反应导致多种细胞信号通路的激活参与调节呼吸、代谢、细胞生存等.在哺乳动物体内,HIFs是主要的低氧应激转录因子,其α亚基受到多种因素的影响,如PHDs、FIH1、线粒体、CHIP,本文将在常氧和缺氧状态下,对HIF稳定性调节机制及缺氧所介导相关信号转导通路进行综述.     

HIFs、PPARs及AMPK在低氧训练减控体重中的调节机制

低氧暴露激活低氧诱导因子(hypoxia inducible factors, HIFs),从而上调其靶基因的表达,包括糖代谢相关蛋白如葡萄糖转运蛋白(glucose transporters, GLUTs)和糖酵解相关酶如乳酸脱氢酶A (lactate dehydrogenase A, LDHA)、醛缩酶A (aldolase A, ALDA)等基因,因此HIFs参与葡萄糖氧化分解供能,在介导机体低氧应答过程及减控体重中起重要作用。运动训练可激活过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors, PPARs),其参与调控脂肪酸代谢、胰岛素敏感性及机体能量平衡,对于减控体重具有积极作用;另外,低氧暴露或者是运动训练均可激活细胞内能量感受器AMP激活的蛋白激酶(5’-AMP activated protein kinase, AMPK),促进葡萄糖和脂肪酸氧化进程,促进肥胖机体减控体重。研究表明,相比于单纯低氧暴露或运动训练,低氧训练的双重刺激更有利于减控体重。低氧训练激活HIFs、PPARs及AMPK,这三种因子作为糖脂代谢的关键调控因子,是否在低氧训练减控体重过程中存在叠加效应?本文结合前人研究,综述HIFs、PPARs及AMPK三者在低氧训练下的相互作用,以及以AMPK-HIFs轴和AMPK-PPARs轴为核心的低氧训练减控体重的可能机制,为低氧训练应用于减控体重实践提供理论依据。     

人体肝癌细胞急性低氧及低氧习服差异表达基因分析

本文分析了人体肝癌细胞(HepG2)急性低氧处理以及低氧习服处理后基因表达谱的改变。急性低氧处理为细胞在1％氧气中培养48h,低氧习服处理为细胞在1％氧气中培养24h,常氧培养24h,以此作为一个周期,重复6个周期。联合应用抑制消减杂交技术和cDNA芯片技术,筛选HepG2细胞经急性低氧处理与正常培养细胞相比差异表达的基因,以及经低氧习服处理细胞与正常培养细胞相比差异表达的基因。结果显示,HepG2细胞经急性低氧处理与在常氧条件下培养相比,差异表达的基因有37个,表达水平全部表现为下调,其中包括参与细胞周期、细胞应激、细胞信号转导、细胞骨架形成、转录相关蛋白及细胞代谢相关蛋白的基因,1个未知基因序列、4个EST序列、5个线粒体蛋白基因,另外有功能不明的蛋白质基因12个。低氧习服处理的细胞与常氧条件下培养的细胞相比,差异表达的基因有6个,其中包括两个线粒体蛋白基因、金属蛋白酶1基因、转铁蛋白基因、Thymosin ．beta-4和TPT1基因。其中线粒体蛋白ND4、转铁蛋白、Thymosin.beta-4和TPT1基因的表达呈上调,线粒体NDl及金属蛋白酶1基因的表达水平呈下调。经低氧习服处理后,细胞低氧耐受力提高,低氧习服处理细胞基因的表达与急性低氧处理细胞和正常培养细胞的基因表达不同,这种变化可能与低氧习服细胞低氧耐受力的增强有关。     

多种翻译后修饰对低氧诱导因子-1α稳定性调控的机制

低氧诱导因子-1（hypoxia-inducible factor-1, HIF-1）是组织细胞对缺氧感应和调控的一类关键转录因子,在机体中广泛表达.作为细胞低氧应答反应中的重要调节因子,HIF-1能够调节100多种涉及低氧应激下细胞适应和存活的靶基因. HIF-1是由氧依赖的α亚基和细胞内稳定表达的β亚基构成的异源二聚体.其中α亚基对氧浓度变化敏感,是HIF-1的功能性亚基,它的表达活性决定了HIF-1的生物学活性.近期研究发现,HIF-1α的一系列翻译后修饰可改变其稳定性,进而调控其转录激活活性,从而参与肿瘤、低氧性肺动脉高压以及心血管疾病等的发生与发展.本文主要就HIF-1α的一列系翻译后修饰,如羟基化、泛素化、磷酸化、乙酰化、SUMO化修饰作一综述.     

膜铁转运蛋白1，铁调素的靶分子？

膜铁转运蛋白1是重要的跨膜铁输出分子,主要分布于十二指肠和单核巨噬系统的细胞膜上,参与机体的肠铁吸收和巨噬细胞对铁的再循环等过程。铁调素是调节机体铁代谢平衡的激素,机体通过肝脏分泌的铁调素对铁转运相关蛋白的表达进行调控,从而实现机体自身的铁稳态。最新研究显示,铁调素的靶分子可能是膜铁转运蛋白1,它通过直接的作用引起膜铁转运蛋白1的内化(internalization)、降解,从而调节其在细胞膜上的表达量,进而控制肠铁吸收和巨噬细胞对铁的再循环过程,以维持机体的铁稳态。     

鼠伤寒沙门菌感染巨噬细胞铁稳态相关基因mRNA表达谱

用荧光定量PCR法检测鼠RAW264.7巨噬细胞感染与未感染鼠伤寒沙门菌后18种铁穗态相关基因的表达,评估宿主与病原体相互作用中铁稳态效应。研究显示,活的鼠伤寒沙门菌感染巨噬细胞1 h后可以诱导转铁蛋白受体表达,引起细胞内动态铁池相关基因的mRNA水平上长。基因表达分析显示,沙门菌通过诱导铁氧还原酶(Steap3)、铁膜转运蛋白(Dmt1)、铁调节因子Tfr2/Hfe以及铁调节蛋白(Irp1和Irp2)的表达主动吸收铁,而经铁转运蛋白(Fpn1)的铁外流并无明显改变。沙门菌在感染后1h积极地驱动了转铁蛋白介导的铁吸收程序。     

组蛋白赖氨酸甲基转移酶2D调控H9c2细胞中HIF-1α/VEGF通路

组蛋白赖氨酸甲基转移酶2D (histone-lysine N-methyltransferase 2D, KMT2D) 作为主要的组蛋白3第4位赖氨酸 (H3K4) 甲基转移酶,在调控胚胎发育、组织分化、代谢和肿瘤抑制方面发挥重要作用。在小鼠体内,敲除Kmt2d会导致严重的心脏发育缺陷最终造成胚胎期死亡。低氧诱导因子-1α (hypoxia-inducible factor 1α, HIF-1α) 作为调节细胞应对低氧的关键转录因子,能够调控多种下游基因转录。有相关研究揭示,表观遗传调控者能够调节HIF-1α的稳定性和活性。同样,作为表观遗传调控者的组蛋白甲基转移酶KMT2D是否参与低氧条件下HIF-1α对下游基因的调控,目前仍未知。在本研究中,观察在Kmt2d正常或缺乏的情况下,心肌细胞H9c2对低氧环境的应答反应。结果显示,与常氧条件相比,低氧状态下HIF-1α、组蛋白乙酰化酶P300、KMT2D及其介导的H3K4一甲基化 (H3K4 mono-methylation, H3K4me1)的蛋白质水平增加 (P<0.05);HIF-1α下游基因血管内皮生长因子 (vascular endothelial growth factor, Vegf) 的mRNA表达水平明显上调 (P<0.01)。染色质免疫共沉淀实验 (chromatin immunoprecipitation assay, ChIP-qPCR) 检测结果显示,H3K4me1和组蛋白3第27位赖氨酸乙酰化 (histone 3 lysine 27 acetylation, H3K27ac) 在Vegf基因启动子区域的结合丰度明显增加 (P<0.05)。低氧条件下沉默Kmt2d之后,H3K4me1蛋白水平和Vegf的mRNA表达下降 (P<0.05)。本研究表明,低氧条件下KMT2D参与调控HIF-1α和下游基因Vegf的表达。     

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。     

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 uptake and metabolism in the new millennium

Iron is an essential element for metabolic processes intrinsic to life, and yet the properties that make iron a necessity also make it potentially deleterious. To avoid harm, iron homeostasis is achieved through iron transport, storage and regulatory proteins. The functions of some of these molecules are well described, for example transferrin and transferrin receptor-1, whereas the roles of others, such as the transferrin homolog melanotransferrin, remain unclear. The past decade has seen the identification of new molecules involved in iron metabolism, such as divalent metal transporter-1, ferroportin-1, hepcidin, hemojuvelin and heme carrier protein-1. Here, we focus on these intriguing new molecules and the insights gained from them into cellular iron uptake and the regulation of iron metabolism.     

铁自噬与铁死亡及其相关疾病

铁是血红素、线粒体呼吸链复合体和各种生物酶的重要辅助因子,参与氧气运输、氧化还原反应和代谢物合成等生物过程。铁蛋白(ferritin)是一种铁存储蛋白质,通过储存和释放铁来维持机体内铁平衡。铁自噬(ferritinophagy)作为一种选择性自噬方式,介导铁蛋白降解释放游离铁,参与细胞内铁含量的调控。适度铁自噬维持细胞内铁含量稳定,但铁自噬过度会释放出大量游离铁。通过芬顿 (Fenton)反应催化产生大量的活性氧(reactive oxygen species, ROS),发生脂质过氧化造成细胞受损。因此,铁自噬在维持细胞生理性铁稳态中发挥至关重要的作用。核受体共激活因子4 (nuclear receptor co-activator 4, NCOA4)被认为是铁自噬的关键调节因子,与铁蛋白靶向结合,并传递至溶酶体中降解释放游离铁,其介导的铁自噬构成了铁代谢的重要组成部分。最新研究表明,NCOA4受体内铁含量、自噬、溶酶体和低氧等因素的调控。NCOA4介导的铁蛋白降解与铁死亡(ferroptosis)有关。铁死亡是自噬性细胞死亡过程。铁自噬通过调节细胞铁稳态和细胞ROS生成,成为诱导铁死亡的上游机制,与贫血、神经退行性疾病、癌症、缺血/再灌注损伤与疾病的发生发展密切相关。本文针对NCOA4介导的铁自噬通路在铁死亡中的功能特征,探讨NCOA4在这些疾病中的作用,可能为相关疾病的治疗提供启示。     

Iron regulatory protein 1 as a sensor of reactive oxygen species

Iron regulatory proteins (IRP1 and 2) function as translational regulators that coordinate the cellular iron metabolism of eukaryotes by binding to the mRNA of target genes such as the transferrin receptor or ferritin. In addition to IRP2, IRP1 serves as sensor of reactive oxygen species (ROS). As iron and oxygen are essential but potentially toxic constituents of most organisms, ROS-mediated modulation of IRP1 activity may be an important regulatory element in dissecting iron homeostasis and oxidative stress. The responses of IRP1 towards reactive oxygen species are compartment-specific and rather complex: H2O2 activates IRP1 via a signaling cascade that leads to upregulation of the transferrin receptor and cellular iron accumulation. Contrary, superoxide inactivates IRP1 by a direct chemical attack being limited to the intracellular compartment. In particular, activation of IRP1 by H2O2 has established a new regulatory link between inflammation and iron metabolism with new clinical implications. This mechanism seems to contribute to the anemia of chronic disease and inflammation-mediated iron accumulation in tissues. In addition, the cytotoxic side effects of redox-cycling anticancer drugs such as doxorubicin may involve H2O2-mediated IRP1 activation. These molecular insights open up new therapeutic strategies for the clinical management of chronic inflammation and drug-mediated cardiotoxicity.     

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

Our 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.