HMGB1在部分肝脏疾病的研究进展

高伟东，彭慈军，李阳,吴波，耿新

（遵义医学院附属医院肝胆外科，贵州省遵义市 563000）

【摘要】 高迁移率族蛋白B1（high-mobility group protein B1, HMGB1）是一种广泛分布于真核细胞中，由215个氨基酸组成的高度保守的DNA结合蛋白。常态下，参与基因转录、DNA修复、重组、复制及细胞运动等多种生物学过程。组织损伤时，HMGB1 可由激活的免疫细胞主动分泌和/或由坏死细胞被动释放至细胞外，作为内源性危险信号激活机体免疫系统，介导无菌炎症反应。HMGB1自被发现以来经过大量研究发现其参与肝脏多种疾病发病机制，且具有关键作用。本文就HMGB1在肝缺血再灌注、肝癌、肝纤维化中所起的作用作一综述。

【关键词】HMGB1；组织损伤；炎症；肝缺血再灌注；肝癌；肝纤维化

【中图分类号】R657.3

Progress of HMGB1 in liver diseases 

Gao Weidong, Peng Cijun,li Yang, Wu Bo, Geng Xin

(Department of Hepatobiliary Surgery,Affiliated Hospital of Zunyi Medical College，Zunyi,Guizhou,56300,China)

【Abstract】 High-mobility group protein B1（HMGB1）, a highly conserved DNA binding protein composed of 215 amino acids, is widely distributed in eukaryotic cells. Under normal conditions, they are involved in various biological processes, such as gene transcription, DNA repair, recombination, replication and cell movement. In the case of tissue damage, HMGB1 can be actively secreted by activated immune cells and/or passively released from the necrotic cells to the outside of the cell, acting as an endogenous risk signal to activate the body's immune system and mediate the sterile inflammatory response. Since its discovery, HMGB1 has been widely studied and found to be involved in the pathogenesis of various liver diseases and plays a key role.This paper reviews the role of HMGB1 in hepatic ischemia reperfusion, liver cancer, and liver fibrosis.

【key word】  HMGB1；tissue injury；inflammation；hepatic ischemia reperfusion；liver cancer；liver fibrosis

1、HMGB1的结构

HMGB1是HMGB家族中的一员，于1973年首次发现并报道^[1]，其在生物进化中高度保守，人类和老鼠的HMGB1序列相同部分达到98%。HMGB家族有HMGB1、HMGB2、HMGB3三种蛋白（起初发现HMGB4时认为是HMGB家族新的成员，后来发现其与HMGB3相同，又将其重命名为HMGB3^[2]，三种 HMGB含有80%相同的氨基酸序列，HMGB1存在于几乎所有真核细胞中，HMGB2仅存在于淋巴组织中及成年动物的睾丸中，HMGB3仅在胚胎及造血干细胞中表达^[3-4]。HMGB家族中尤以对HMGB1研究最为多。HMGB1是HMGB家族最先发现的成员，是一种广泛分布于真核细胞生物体内的一种非组蛋白^[5]，分子量为25-30KDa^[1]， 由215个氨基酸和3个结构域组成，3个结构域分别为A-BOX（9-79个氨基酸），B-BOX（95-163个氨基酸），C端酸性尾巴（186-215个氨基酸）^[6]。HMGB1的B-BOX是介导炎症反应的部位，而A-BOX为HMGB1的拮抗剂。在A-BOX和 B-BOX中分别含有一个核定位序列（ nuclear localization sequence，NLS），其中A-BOX的NLS含有4个保守的赖氨酸残基，B-BOX的NLS含有5个保守的赖氨酸残基，赖氨酸残基容易发生乙酰化修饰，导致HMGB1由胞核释放到胞质^[7]。， HMGB1含有三个氧化还原敏感的半胱氨酸残基分别位于23、45、106位点，23和45位点的半胱氨酸残基位于A-BOX上，106位点的半胱氨酸残基位于B-BOX上，这三个位点的半胱氨酸残基的氧化还原状态对HMGB1的功能和活性有重要作用，三个位点的半胱氨酸残基都是还原状态的HMGB1可以和CXCL12结合通过CXCR4刺激免疫细胞向炎症组织移动，当HMGB1部分氧化时，即A-BOX上两个半胱氨酸残基氧化形成二硫键，B-BOX上106位点半胱氨酸残基依旧是还原状态，此时A-BOX上的两个半胱氨酸残基形成的二硫键可以与TLR4/MD-2结合，介导巨噬细胞中TNF、NF-KB等的活化^[8]。  一旦HMGB1上所有半胱氨酸残基都发生氧化会使HMGB1的生物学活性丧失^[9-10]。由此可见106位点的半胱氨酸残基的氧化还原状态对HMGB1的活性至关重要，23及45位点上半胱氨酸残基的状态决定了HMGB1的功能。

2、HMGB1的功能

HMGB1最早仅被描述为一种DNA结合蛋白，作为辅因子参与DNA的转录调节^[11-12]。在之后对其不断的研究中发现HMGB1作为一种促炎因子参与多种炎症反应^[13]。正常情况下HMGB1存在于细胞核中，HMGB1 在细胞核内以脱乙酰化的形式存在^[14]，当细胞受到损伤的时候在HMGB1的两个核定位序列之间的部分经乙酰化修饰从DNA上脱离下来释放到胞质中，再释放到胞外，介导炎症反应。核内的HMGB1具有稳定核小体结构、调控转录因子与 DNA 相应序列结合的功能，参与基因转录、DNA 修复、重组、复制等多种生物学过程^[15]，胞内的HMGB1参与细胞自噬反应以及囊泡形成^[16-17]，胞外的HMGB1被认为是细胞损伤或感染后发生炎症的重要介质^[18]。HMGB1由细胞内分泌到细胞外有两条途径，一条是由免疫细胞主动分泌，例如巨噬细胞，自然杀伤细胞等，另一条是由坏死细胞被动分泌^[19]。释放到胞外的HMGB1可以和高度糖基化终产物受体（receptor for advanced glycation end products， RAGE）、Toll 样受体(toll-like receptor) 2、4、9结合^[20-25]，促使细胞释放ROS、趋化因子（CXCL10、 CXC12）、细胞因子（如TNF-α、 IL-1β）等炎性信号，从而激活组织炎症反应。向健康的动物体内注射HMGB1会导致原本健康的动物出现炎症反应的相关症状，例如发热、体重减轻、厌食、急性肺损伤^[26]，炎症反应的动物模型给予HMGB1拮抗剂后炎症反应减轻^[27-28]。

3、HMGB1在肝缺血再灌注损伤中的作用

肝缺血再灌注损伤（hepatic ischemia reperfusion injury, HIRI）是指在肝脏阻断血流供应一段时间后恢复血流供应，肝脏功能和结构的损伤不仅没有减轻，反而加重的现象。HIRI病理生理过程包括两部分，第一部分是肝脏缺血、缺氧导致的肝脏细胞肿胀坏死，第二部分是肝脏在恢复血流供给、细胞复氧后导致的损伤^[29]。在肝脏手术中，尤其是肝叶切除、肝移植不可避免的需要阻断肝脏的血流供应，在恢复血供后肝脏发生HIRI，导致缺血肝脏坏死或移植的肝脏失活，影响病人术后恢复^[30]。HIRI包括两种类型，一种是热HIRI，常见于肝脏外科手术和失血性休克，另一种是冷HIRI，主要见于肝移植手术，因被移植肝脏需低温保存运输。

细胞外HMGB1是HIRI炎症反应的一个重要中间介质，减少胞外过多的HMGB1，肝脏受损程度会相应减轻，实验动物的死亡率也相应的降低^[31]。在肝缺血再灌注的早期肝实质细胞便主动分泌HMGB1到血液循环中^[32]，缺血再灌注时期，由于产生大量的活性氧（ROS）以及由于ATP功能障碍和细胞膜通透性改变引起的胞内钙离子增多，导致肝细胞坏死，坏死的肝细胞被动释放HMGB1至胞外，释放到胞外的HMGB1可以和肝脏中多种细胞（例如kupffer 细胞、肝实质细胞等）表达的表面受体TLR4/MD2、RAGE和CXCR4结合，这三种受体在肝缺血再灌注中起到重要作用^[33]。胞外的HMGB1和kupffer细胞表面的这三种受体结合介导IFR-3、NFKB等多种细胞因子的活化进而导致TNF、IL-1B、IL-6表达增多，并主动释放HMGB1至胞外，此循环可逐步放大炎症反应导致肝缺血再灌注损伤加重^[34]。虽然胞外HMGB1加重肝脏缺血再灌注损伤，但有研究表明，特异性肝脏HMGB1表达减少的小鼠在肝脏缺血再灌注损伤后肝脏损伤程度会增加，可能胞内HMGB1对肝脏缺血再灌注损伤起到保护作用^[35]。

4、HMGB1在肝癌中所起的作用

肝细胞癌（hepatocellular carcinoma， HCC）是我国最常见的恶性肿瘤之一，国家癌症中心发布的新的报告指出在我国肝癌发病率排在第五位，而死亡率排在第二位。肝癌作为一种高发癌症严重威胁我国人民生命健康。 尽管肝癌的治疗方法在不断优化，但依然是最难治疗的癌症之一。对于早期肝癌，即使经过手术治疗，5年复发率仍然高达70%^[36]。即使是体积较小（肿瘤直径<3cm）的早期肝癌患者在接受手术后5 年生存率仍不理想^[37-38]。有研究表明肿瘤的生长和肿瘤微环境中持续氧化应激和慢性炎症有关^[39]。在肿瘤中心产生的缺氧环境会导致细胞坏死，进而释放损伤相关模式分子（damage-associated molecular patterns，DAMP），如高迁移率族蛋白B1 (HMGB1)和线粒体DNA (mtDNA)，这些DAMP分子和他们的受体相互作用，引发炎症级联反应，促进肿瘤进展^[40]。在肿瘤细胞缺氧时，HMGB1会释放到胞质中，且被肿瘤细胞主动释放到胞外，胞外的HMGB1可以通过TLR-4途径促进肿瘤细胞的侵袭和转移^[41]，同时HMGB1与肝癌细胞的增殖也有密切，HMGB1不但可以通过增强cyclin D1和PCNA的表达介导HCC的增殖^[42]，同时还可控制肝癌的分化、大小、AFP的水平^[43]。 HMGB1对AFP水平的影响显示其可能成为诊断肝癌的一种潜在方式。有趣的是HMGB1还通过抑制p38依赖性线粒体通路诱导HCC细胞凋亡，可见HMGB1在肝癌中的作用是矛盾的，即作为一种肿瘤抑制因子，又可作为一种肿瘤促进因子^[44]。另外，不仅是肝癌，也有研究证明肺癌^[45-46]，乳腺癌^[47-48]，胃癌^[49]，结肠癌^[50]，也与HMGB1的异常表达有关。   

5、HMGB1在肝纤维化中的作用

 肝纤维化（hepatic fibrosis）是由多种原因导致的慢性肝损伤，造成肝纤维化的原因包括病毒感染（尤其以乙型肝炎病毒感染最为常见）、肝脏自身免疫性疾病、非酒精性脂肪性肝炎等，肝纤维化是演变为肝硬化和肝癌的一条重要途径^[51]。肝纤维化是一个可逆的病理过程，阻止肝脏纤维化的进展是改善各种肝病预后的一条重要策略。肝星状细胞（hepatic stellate cells ，HSCs）在肝纤维化中起到关键作用，在炎症因素等的刺激下，处于静止状态的肝星状细胞转变为活化的肌成纤维细胞，肌成纤维细胞具有致炎、收缩和纤维形成作用。细胞外基质（ECM）的异常积累是肝纤维化的一个重要特征，ECM包括胶原、糖蛋白、蛋白多糖。在纤维化的肝脏中胶原的含量是正常肝脏的6倍。韩红莉等^[52]证明HMGB1可以刺激HSCs分泌ECM，且随着HMGB1浓度增加，刺激作用加强，并可与活化的HSCs表达的TLRs和RAGE结合增加肝纤维化程度。自噬是在进化过程中相对保守的一个过程，可以保持细胞器的新陈代谢，在促进HSCs活化和产生ECM中起到重要作用^[53]，有研究表明当HSCs活化时自噬潮会相应增加，抑制自噬可一定程度上抑制HSCs的活化^[54]，当去除自噬抑制剂后会恢复HSCs的活化^[55]。通过CCl4介导引起肝硬化小鼠的血清中HMGB1可以增强小鼠原代HSCs的增殖和自噬^[56]。由此可推测HMGB1可通过抑制肝星状细胞活化和减弱自噬作用来减弱肝纤维化，可能是逆转肝纤维化程度，阻止肝脏进一步病变的潜在治疗靶点。

6、以HMGB1为靶点的一些治疗措施

随着对HMGB1认识的不断增加，越来越多的数据证实HMGB1可以作为一种治疗肝病靶点，将HMGB1拮抗剂用于药物诱导产生肝衰竭的小鼠后，HMGB1水平和肝脏损伤程度降低，小鼠存活率升高^[57]。氢气可以减弱脓毒血症导致的肝损伤，同时伴随着氧化产物和血清中HMGB1含量下降^[58]。阿托伐他丁可以降低非酒精性脂肪肝小鼠肝脏缺血再灌注损伤后血清中HMGB1的水平和TLR4的表达，从而减轻肝脏损伤^[59]。Yamamoto T.等^[31]报道了采用吸附柱吸附肝缺血再灌注后的大鼠血清中过量的HMGB1减轻了肝脏损伤。这些报道证实了抑制HMGB1表达或者去除多余HMGB1都能够减轻肝脏损伤，为临床治疗肝缺血再灌注损伤提供了新的方式。

7、小结与展望

HMGB1在肝脏缺血再灌注、肝癌和肝纤维化的发病机制中起到重要作用，随着对HMGB1的研究不断增加，发现HMGB1还参与脓毒症^[60]、关节炎^[61]、糖尿病^[62]等疾病的发生 。若在发病早期或者提前抑制HMGB1的释放，有望减轻损伤程度，到目前为止已有许多文章报道各种方式减少或抑制HMGB1释放，但只是在动物模型及体外细胞实验中开展并取得了较好效果，但应用于人体后会怎么目前尚无报道，有待进一步研究。根据目前文献报道情况来看HMGB1在肝癌、纤维化、缺血再灌注方面起到重要作用，针对HMGB1的各种研究应更加深入，以期HMGB1可以成为防治肝脏疾病的重要靶点，造福于患者。

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