修回日期: 2021-07-29
接受日期: 2021-09-13
在线出版日期: 2021-11-08
非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)是一个与代谢综合征相关的日益扩大的健康问题. 肝窦内皮细胞(liver sinusoidal endothelial cells, LSECs)是位于血液与其他肝细胞类型之间高度专业化的内皮细胞, 由窗孔组成, 具有高内吞能力, 并在维持肝脏整体稳态中发挥重要作用. 病理条件下LSECs可能是多种慢性肝病的关键事件. 本篇综述介绍了LSECs的独特生理结构和功能, 重点总结了NAFLD中LSECs的主要变化(包括肝窦毛细血管化、血管生成、血管收缩、促炎和促纤维化)及其发生机制, 还涉及LSECs对NAFLD进展的影响, 旨在说明LSECs靶向治疗对NAFLD具有潜在疗效.
核心提要: 在非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)中, 肝窦内皮细胞(liver sinusoidal endothelial cells, LSECs)最早最显著的形态学改变为毛细血管化. 而与血管生成、炎症、纤维化相关的分子事件也出现于早期脂肪变性阶段. LSECs的结构功能改变又能导致NAFLD的进展与恶化.
引文著录: 曹婕露, 严峻彬, 吴锦婷, 陈芝芸. 肝窦内皮细胞与非酒精性脂肪性肝病的研究进展. 世界华人消化杂志 2021; 29(21): 1254-1260
Revised: July 29, 2021
Accepted: September 13, 2021
Published online: November 8, 2021
Nonalcoholic fatty liver disease (NAFLD) is a growing health problem associated with metabolic syndrome. Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells located between the blood and other liver cell types. They are composed of window pores, have high endocytosis, and play an important role in maintaining the overall liver homeostasis. Under pathological conditions, LSECs may be the key event of a variety of chronic liver diseases. In this review, we introduce the unique physiological structure and function of LSECs, summarize the main changes of LSECs in NAFLD (including sinohepatic capillarization, angiogenesis, vasoconstriction, proinflammatory effect, and fibrosis) and their pathogenesis, and discuss the influence of LSECs on the progression of NAFLD, with an aim to demonstrate the potential efficacy of LSECS targeted therapy for NAFLD.
- Citation: Cao JL, Yan JB, Wu JT, Chen ZY. Research progress of sinusoidal endothelial cells in nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2021; 29(21): 1254-1260
- URL: https://www.wjgnet.com/1009-3079/full/v29/i21/1254.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v29.i21.1254
非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)是一种与胰岛素抵抗(insulin resistance, IR)和遗传易感性密切相关的, 由代谢应激诱导的疾病, 主要包括非酒精性肝脂肪变性和非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)[1]. 约22%的NASH患者会进展至晚期纤维化[2]. 虽然生活方式的改变可以控制风险因素, 但目前还没有可用于治疗NAFLD的特效药物疗法.
近年来NAFLD的发病机制已得到广泛研究, "多重打击"假说认为多种损伤共同作用于遗传易感性受试者可诱发NAFLD, 其中首要的"打击"因素为肝细胞的胰岛素抵抗和脂肪毒性[3]. 有研究表明除了骨骼肌、脂肪组织和肝细胞外, 膳食脂肪可诱导肝窦内皮细胞(liver sinusoidal endothelial cells, LSECs)的胰岛素抵抗[4]. 同时, 氧化应激、脂肪毒性和肠道细菌内毒素等"打击"因素也能加重LSECs损害、促进NAFLD病理变化[5]. 因此, LSECs可能为NAFLD的发病机制中的一个重要环节.
肝脏由实质细胞和非实质细胞构成, 在非实质细胞中, 内皮细胞(endothelial cells, ECs)所占比例最大. 小鼠肝脏中ECs约占所有标记细胞的22%, 仅次于肝细胞[6]. 大多数ECs沿肝窦非连续性排列, 这一部分被为LSECs. LSECs是肝星形细胞和肝细胞之间、肝脏脂肪组织与肠道血液之间高度专业化的内皮细胞[7], 生理状态下是维持肝脏稳态的守门人, 而病理条件下在慢性肝病的发生和发展中起关键作用[8]. 本篇综述简要介绍了稳态条件下LSECs独特的生理结构和生理功能, 讨论了NAFLD进展的主要阶段中LSECs的病理变化(包括毛细血管化、血管生成、血管收缩、促炎和促纤维化)及其影响因素, 还涉及以上结构功能改变如何推动疾病的恶化, 总结了相关的信号通路, 提出了LSECs靶向治疗的可行性.
LSECs在结构上具有多方面的独特性, LSECs形成肝窦壁, 通过特殊的细胞间连接紧密连结, 内含大量跨膜的直径约为50-150 nm的窗孔[9]. 窗孔在其生命周期内能不断改变其位置和直径, 甚至通过开合来调控细胞内外物质和信息的交换[10]. 肌动蛋白、纤连蛋白、肌球蛋白和钙调蛋白组成LSECs的细胞骨架, 在窗孔的动态改变中起着重要作用. 细胞松弛素B、细胞松弛素D可促进肌动蛋白解聚[9,11]. LSECs表面覆盖着多种清除受体, 以识别内部和外部危险相关的分子, 细胞质中含有具有摄取功能的囊泡和细胞器, 运输和降解内吞的物质.
这种独特的结构使得LSECs具有高渗透性和强内吞能力, 在正常肝脏中, LSECs可以充当血浆蛋白、脂蛋白、代谢物、小乳糜微粒残余物、病毒颗粒和其他直径小于窗孔的纳米颗粒的选择性屏障[12]. LSECs通过选择性渗透、内吞这两种方式调节脂质转移[13], 在血液与肝实质的脂质交换、乃至全身脂质体内平衡中起着至关重要的作用. LSECs还是控制白细胞进入肝实质的屏障, 发挥抗炎的作用[14].
LSECs通过旁分泌作用协调肝再生和抑制炎症、纤维化. 在部分肝切除的小鼠中, LSECs通过释放血管分泌因子Wnt2和肝细胞生长因子(hepatocyte growth factor, HGF)诱导肝血管新生, 从而促进肝细胞增殖与肝再生[15]. LSECs能维持肝脏稳态, 保持肝星状细胞(hepatic stellate cells, HSCs)和库普弗细胞(kupffer cells, KCs)的静止状态[16]. 此外, LSECs的旁分泌作用也体现在释放包含特定信号分子的 "微囊泡"和外泌体, 目前对这两种结构的认识尚在初始阶段, 已有研究证明成纤维细胞生长因子(fibroblast growth factor, FGF)信号对"信号囊泡"的释放具有重要意义[17].
LSECs也是一种重要的机械传感器[18], 能够响应增加的血流剪应力产生血管扩张剂, 以减轻血压的增加, 此过程由内皮特异性转录因子KLF2介导[19]. 最近还发现血管灌注和血管壁的机械拉伸会激活LSECs中的β1整合素和血管内皮生长因子受体3(vascular endothelial growth factor receptor 3, VEGFR3)信号轴, 诱导HGF表达, 触发肝细胞的增殖[20].
在稳态条件下, LSECs表现出强内吞能力、抗炎和抗纤维化的表型, 它们还调节血管生成和再生, 并且根据内环境机械力的变化调节血管舒张[8]. 一些研究表明, 在NAFLD早期阶段, LSECs具有很强的适应性, 能发挥一定的抗炎作用. Kus等[21]发现, 在高脂饮食诱导的NAFLD小鼠模型中, LSECs的窗孔直径增加, 但数量得以保留; 抗炎性前列腺素的激活释放、炎症负调节因子MCPIP1基因过度表达可能抵消炎症的发生, 连同LSECs对生物能增减的适应性, 可能会在减缓NAFLD进程, 但不排除在细胞分离过程中窗孔数目改变的可能性. 短时间(16 h)暴露于游离脂肪酸的人类和小鼠LSECs, 通过MAPK依赖途径下调参与单核细胞和巨噬细胞招募的促炎趋化因子[22]. 尽管如此, 更多的研究表明, 在遭受持续性肝损伤后, LSECs会迅速改变其结构和功能, 从而损害肝脏的再生反应.
在损伤刺激下, LSECs最早最显著的形态学改变被认为是肝窦毛细血管化, 其特征是是窗孔的缺失并伴随基底膜基质在LSECs的管腔表面异常沉积[21]. Miyao等[23]证明毛细血管化可能普遍发生于肝单纯脂肪变性到NASH早期阶段的过程中, 并逐渐恶化至NASH晚期. 毛细血管化的影响因素尚未完全确定, 可能与饮食中能量多少[24]和营养物质的分布[25]有关. 后者影响体内肠道菌群和游离脂肪酸的变化, 与LSECs开窗的孔隙率之间存在联系[25]. 由细胞外基质和间质胶原在Disse空间中沉积而形成的基底膜也有助于窗孔的丢失和关闭, 从而阻碍了新陈代谢的交换并加重了肝细胞缺氧, 这是HSCs激活和纤维化的有力触发[16].
毛细血管化的确切机制尚未完全阐明, 但已确定了几种途径. HSCs和肝细胞分泌血管内皮生长因子(vascular endothelial growth factor, VEGF)通过NO依赖和非依赖机制维持LSECs开窗[26], 这是可能最广为人知的机制. 参与调控毛细血管化的信号通路还包括Notch信号通路[27]、Hedgehog (Hh)信号通路[28-30], 前者通过调节 eNOS/sGC和DLL4过表达等促进毛细血管化, 后者通过调节肝X受体和BMP9等参与毛细血管化[16].
另一方面, 毛细血管化的LSECs显示出其内吞能力的显著下降, 影响肝脏对各种脂蛋白的摄取[28], 导致高脂蛋白血症并加重肝脏脂肪变性[31]. 质膜囊泡相关蛋白是内皮窗孔形成所需的内皮特异性整合膜糖蛋白, 其减少能导致LSECs通透性的降低, 缺乏质膜囊泡相关蛋白的小鼠中LSECs窗孔数目的显著减少, 从而引发广泛的肝脂肪变性[31]. 毛细血管化的LSECs不仅改变其结构, 而且改变其自分泌和旁分泌活性, 打破其产生血管扩张剂和血管收缩剂的平衡, 使之向血管收缩剂的方向转移, 降低NO的生成及其生物利用度[32].
内皮功能障碍是所有血管床都存在的一种病理状态, 最初被定义为血管对特定刺激的舒张功能受损[33]. 在肝损伤过程中, LSECs产生的血管扩张剂(如NO、环氧合酶等)减少、血管收缩剂(如内皮素1、血栓素A2等)增加[16]. 由于NO可能是调节肝脏血管张力的最重要的血管扩张剂, 因此LSECs内皮功能障碍主要表现为内皮一氧化氮合酶(endothelial NO synthase, eNOS)活性降低[34], 继而发生与血管阻力增加相关的脂肪变性. Francque等[35]报告了大鼠模型中患有严重NAFLD的大鼠门静脉压力显著升高, 而门静脉压力的增加与严重脂肪变性的发展相一致. 而在肝硬化的情况下, 除了eNOS活性降低以外, 超氧化物歧化酶(superoxide dismutase, SOD)的增加能促使超氧化物与NO反应, 形成一种强有力的促纤维化剂-过氧亚硝酸盐, 进一步降低NO的利用率[36].
内皮功能障碍发生在NAFLD脂肪变性的早期阶段, 并在晚期肝硬化中持续存在[34,37,38]. 研究人员观察到喂养高脂饮食6 kw的小鼠肝脏显示出与炎症或纤维化无关的肝血管阻力增加、NO活性降低和氧化应激增加, 这些变化是在没有炎症和纤维化的情况下出现的[38]. 肝硬化的大鼠肝脏表现出内皮功能障碍, 表现为对乙酰胆碱的舒张度明显低于对照组肝脏[39].
LSECs功能的破坏可能在肝脏病理生理中起着重要作用. 在NAFLD中, 内皮功能障碍能导致肝脂肪变性恶化和肝纤维化. 实验证明NO缺失导致肝脏大量脂肪沉积[40]、促进HSCs向促纤维化表型的激活[41]. 其机理可能与NO通过亚硝基化调节蛋白质功能和信号传导, 抑制脂肪酸生成和脂肪酸有效β氧化等有关[42]. NO的减少也可能在肝纤维化进程中发挥作用, NO已被证明可以维持HSCs的静止状态, 减少HSCs暴露于NO的时间可促进其激活[41]. 向共培养的LSECs和HSCs中加入eNOS抑制剂L-NAME也能抑制LSECs维持HSCs静止的能力[43].
在药物的治疗上, 一种肝选择性NO供体, V-PYRRO/NO能改善NAFLD小鼠模型的肝脂肪变性和餐后葡萄糖耐量[44]. 他汀类药物降低门静脉压力的有益效果已经在肝硬化患者中得到证实[45], 其潜在分子机制可能与上调肝内皮KLF2衍生的转录程序提供血管保护有关, 如诱导eNOS和血栓调节素生成.
血管生成, 是指从先前存在的血管床形成新生血管的过程[46], 毛细血管化与慢性炎症一起促进血管生成, 窗孔的丧失致使缺氧的出现, 诱导缺氧诱导因子(hypoxia inducible factor-1, HIF)积累, 从而刺激周围细胞产生血管生成因子, 启动新血管形成[46-48]. 在对氧化应激的反应中, LSECs本身也可以通过直接分泌VEGF、TNF-α、血管生成素2(angiopoietin-2, Ang-2)和各种类型的Wnt配体及Frizzled(Fz)家族受体来促进血管生成[16].
与血管生成相关的分子事件始于简单脂肪变性, 但实质性的血管生成开始于在NASH阶段[7]. 肝脏单纯脂肪变性患者和经活检证实的NASH患者的血清Ang-2水平高于健康人[49]. 在NASH动物模型中, 不仅VEGF和CD105的表达增加, 还能观察到肝脏正常血管系统被破坏[50].
血管生成的触发因素包括脂质堆积、脂肪毒性、炎症、组织缺氧等[50]. 血管生成是多种促血管生成介质和效应细胞相互作用的结果, 涉及许多信号通路, 例如VEGF和VEGF受体(vascular endothelial growth factor receptor, VEGFR), Ang2和Tie2受体等. VEGF可刺激内皮细胞增殖并诱导升高微血管通透性, 从肝脂肪变性到NASH的过渡过程中VEGF水平上升, 而抗血管内皮生长因子受体2(vascular endothelial growth factor receptor 2, VEGFR2)治疗可阻断VEGF, 改善肝脏血管系统[50]. 而贝伐单抗是一种适合用作血管生成直接抑制剂的治疗候选药物, 其抗血管生成的功效归因于其结合VEGF-A的能力[51]. 血管生成素(主要是ANG1和ANG2)通过Tie受体传导信号来调节正常的血管生成, 在炎症介质的环境中, ANG2成为主要的血管生成信号, 抑制Tie2发出维持血管稳态的ANG1信号, 促进新生血管生成, 形成异常的血管系统[52]. 在药物治疗上, 使用L1-10能抑制ANG2信号通路, 从而降低血管密度, 使微血管网络部分正常化[49].
虽然在NAFLD的初始阶段LSECs发挥了抗炎作用, 但随着NAFLD的发展, LSECs逐渐获得促炎表型和促炎功能. 在有损伤刺激的情况下, LSECs分泌大量的细胞因子和趋化因子(如TNF-α, IL-6, IL-1和CCL2)激活KCs[16]. KCs在肝窦毛细血管化后被激活, 进而推动慢性肝损伤的发展[21]. 在简单脂肪变性阶段, 就能发现参与KCs激活的炎症细胞因子、趋化因子(如TNF-α、IL-6和MCP-1)上调[21]. 损伤的肝细胞和炎症细胞释放炎症介质, 能够进一步激活LSECs炎症介质, 使炎症反应持续[53]. LSECs逐渐失去其生理屏障能力, 上调细胞粘附分子ICAM-1、VCAM-1和VAP-1, 招募白细胞, 导致循环白细胞进入肝实质. 经过以上过程, LSECs从耐受性介质转化为强大的免疫刺激剂, 成为肝内炎症的重要组成部分[16].
在减轻肝脏炎症的治疗上, 研究发现使用抗VLA-4抗体抑制VCAM-1配体VLA-4对单核细胞的作用, 可抑制单核细胞在肥胖小鼠的LSECs间的粘附和跨内皮迁移[54].
肝纤维化是肝实质中细胞外基质(extracellular matrix, ECM)过度沉积的结果, 由肝细胞损伤和炎症引起和HSCs激活介导. 如前所述, LSECs毛细血管化、内皮功能障碍会促进纤维化的发展. 质膜囊泡相关蛋白缺失的小鼠显示出LSECs窗孔数量的明显减少, 接着会自发发展为窦周肝纤维化[31]. 将LSECs和HSCs共同培养的实验证明健康的LSECs具有保持HSCs静止的能力, 而在培养环境中加入eNOS抑制剂可阻断该能力[41]. 血管生成也与纤维化联系密切. 敲除血管生成抑制剂脯氨酰羟化酶-2(prolyl hydroxylase-2, PHD2)基因可导致肝纤维化[55]. 另一方面, 阻断血管生成对纤维化消退的作用尚存在争议. 替米沙坦等血管紧张素Ⅱ1型受体阻滞剂(angiotensin Ⅱ type 1 receptor blockers, ARBs)已被证明可通过抑制血管生成减轻NASH中的肝纤维化[56]. 在体内对整联素Avβ3的特异性抑制可减少血管生成, 却会使肝纤维化恶化. 因此血管生成和肝纤维化之间的关系还需要进一步探讨.
肝损伤后, LSECs获得亲纤维化表型, 直接分泌ECM参与纤维化, 分泌促纤维化分子间接调节肝微环境. 它们的直接作用是在持续损伤后响应TGF-β1而合成层粘连蛋白和胶原蛋白[57]. 内皮-间充质转化(endothelial-to-mesenchymal transition, EndMT), 即内皮细胞转化为肌成纤维细胞并促进细胞外基质沉积, 可能是NASH纤维化的一个研究领域. 已有研究描述了酒精或丙型肝炎病毒相关肝硬化患者以及四氯化碳治疗的小鼠的内皮细胞向间充质转化[58], 但对NAFLD中这方面的研究尚有空缺, 值得进一步探索.
LSECs主要通过改变血管扩张剂/血管收缩分子的平衡来调节HSCs的活化. 在肝脏简单脂肪变性阶段, 参与HSCs激活和影响纤维化的因子(如αSMA, TIMP1, IL-1β)以及VEGFR-2的mRNA表达增加[21]. 在NASH中LSECs过表达的VAP1也直接参与HSCs的活化[59]. 在喂食蛋氨酸和胆碱缺乏饮食或高脂肪饮食的小鼠中, 抑制VAP1可减轻肝纤维化[59]. 外泌体是将特定内容物递送至靶细胞来促进细胞间通讯的细胞外囊泡. 研究表明, 来自功能失调的LSECs的外泌体调节HSCs的激活和迁移, 有利于纤维生成[60]. 需要进一步的研究来真正理解外泌体和其在纤维化过程中的作用.
生理状态下, LSECs是维持肝脏稳态的守门人, 富有可开合的窗孔为其独特的结构特征, 在功能上LSECs主要表现出强内吞作用和促血管舒张、抗炎和抗纤维化作用, 并能通过旁分泌作用协调肝再生. 在NAFLD中, LSECs会迅速对损伤做出反应, 最早最显著的形态学改变为毛细血管化. 内皮功能障碍发生于脂肪变性的早期阶段, 并在晚期肝硬化持续存在. 在NASH阶段, LSECs有助于肝血管生成、炎症、纤维化, 事实上, 与以上现象相关的分子事件也出现于早期脂肪变性阶段. 这些现象又相互关联, 如血管生成与纤维化关系密切, 但具体机制还需要进一步探讨. 反过来LSECs的病理变化又能推动NAFLD的进展与恶化. 目前已有多种治疗策略针对治疗功能失调的LSECs, 比如通过抑制Notch或Hh恢复开窗, 通过抗ANG-2、中和VEGF-A或抗VEGFR2抑制血管生成, 通过阻断VLA-4恢复抗炎能力等, 需要进一步明确LSECs功能变化的机制, 为LSECs成为治疗NAFLD新靶点提供依据, 并为肝脏疾病的临床诊断和治疗提供新的方向.
学科分类: 胃肠病学和肝病学
手稿来源地: 浙江省
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科学编辑:张砚梁 制作编辑:张砚梁
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