修回日期: 2010-04-20
接受日期: 2010-04-27
在线出版日期: 2010-05-28
脂肪肝(fatty liver disease, FLD)存在脂肪组织和肝脏等的免疫功能紊乱, 补体参与了肝脏脂质沉积发生发展的全过程. 肝脂肪变性时过多的脂肪细胞分泌的炎性因子可激活补体, 促进脂质沉积并使炎症反应级联放大, 继而激发肝细胞线粒体损伤, 加重脂质在肝细胞内积存. 补体与脂肪肝关系的研究有助于我们对脂肪肝的发病机制进行更深入的认识, C5L2受体拮抗剂的研究有助于研制开发新一代治疗药物. 因此需要进一步了解补体在肝脏代谢性应激状态下的免疫机制, 从而进一步澄清其在FLD发生发展中的作用, 并采取措施预防病变发展.
引文著录: 王燕, 杨耀娴. 补体与脂肪肝研究进展. 世界华人消化杂志 2010; 18(15): 1577-1581
Revised: April 20, 2010
Accepted: April 27, 2010
Published online: May 28, 2010
Patients with fatty liver disease (FLD) exhibit various immunologic abnormalities in the adipose tissue and the liver. Complement plays an important role in the development of FLD. Innate immune dysfunction in the adipose tissue can lead to abnormal production of adipose-derived factors, some of which can activate complement. Complement can not only amplify the inflammatory response and lead to mitochondrial damage, but also inhibit hepatic fat disposal and promote lipid accumulation in hepatocytes. An exploration of the relationship between complement ant the liver can help us have a deep understanding of the mechanisms underlying the pathogenesis of FLD. The antagonists of the C5L2 receptor provide us potential new medicines for FLD. A further study of the role of complement in stress-induced liver remodeling can help clarify the role of complement in the development and progression of FLD.
- Citation: Wang Y, Yang YX. Advances in understanding the role of complement in the pathogenesis of fatty liver disease. Shijie Huaren Xiaohua Zazhi 2010; 18(15): 1577-1581
- URL: https://www.wjgnet.com/1009-3079/full/v18/i15/1577.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i15.1577
脂肪肝(fatty liver disease, FLD)是指弥漫性肝实质细胞大泡性脂肪变性和脂肪(主要是三酰甘油)蓄积为特征的临床病理综合征. 脂肪肝可以演变为脂肪性肝炎(nonalcoholic steatohepatitis, NASH)、肝纤维化和肝硬化[1]. 近来研究发现FLD呈慢性炎症状态, 与免疫系统密切相关, 存在脂肪组织和肝脏的天然免疫功能紊乱[2,3], 补体系统是自身免疫系统的一部分, 参与了肝脏脂质沉积的发生[4]. 研究显示肝脂肪变性时过多的脂肪细胞可分泌多种炎性因子[5], 炎性因子可激活补体并介导一系列的炎症反应[6], 补体又可抑制炎性细胞凋亡[7], 引起上述炎症反应级联放大, 继而引起肝细胞线粒体损伤, 加重脂质在肝细胞内积存[8]. 补体在FLD的形成与演变中发挥重要作用, 本文就其在FLD发病机制中的作用作一综述.
FLD与免疫系统密切相关, 存在脂肪组织和肝脏等的免疫功能紊乱. 补体系统是获得性免疫系统重要的组成部分, 参与了肝脏脂质沉积发生发展的全过程[9]. 自19世纪末发现补体以来, 已明确多数补体分子属β球蛋白, 少数属α球蛋白及γ球蛋白, 补体组分中含量最高的成分是C3, 正常人体血清中达1 200 mg/L, C3含量的高低与总补体含量平行, 其水平是衡量体液免疫的重要指标. 虽然机体不同组织细胞均能合成补体, 但血浆中大部分补体组分由肝细胞合成分泌.
脂肪组织由成熟的脂肪细胞和间质细胞构成, 后者包括与免疫相关的巨噬细胞、淋巴细胞、内皮细胞和未成熟的脂肪细胞(如前脂肪细胞)[10]. 近来研究发现, 脂肪组织作为体内最大的能量贮库, 并不是被动贮存脂肪的惰性组织, 还可能是体内最大的内分泌器官[11,12], 肝脏细胞是产生脂质的主要细胞, 而脂肪组织是储存三酰甘油的主要场所. 脂肪代谢依赖于机体对能量的需要, 并受营养成分、神经及内分泌激素的调节[13]. 近期的研究发现, 脂肪组织不仅能储存能量, 而且还可以分泌产生一些激素和细胞因子, 积极参与能量平衡、神经内分泌及自身免疫的调节[14]. 有研究表明, 脂肪细胞能分泌C3, 表达C3a受体, 其中补体C3加工转化生成促酰化蛋白(C3a desArg77, acylation stimulating protein, ASP)[15-17], ASP进一步刺激脂肪细胞摄取血液中自由脂肪酸(free fatty acid, FFA)促进脂肪细胞合成三酰甘油(triacylglycerol, TG)[18]. 此外, Cianflone等报道在血液游离脂肪酸的刺激下, 促使C3的α链氨基末端上的精氨酸-丝氨酸键断裂, 在补体B参与下生成一分子C3a和一分子C3b. C3a羧基末端上的精氨酸(Arg)迅速被羧基肽酶B(carboxypeptidase B, CPB)移去, 从而生成76个氨基酸肽链的酰化刺激蛋白, 而C3裂解产生的C3b重新进入循环, 从而不断扩大循环[19]. C3a与ASP可结合受体C5L2, 并促进TG的合成[20-22]. 血清ASP浓度随进食不断上升,并促进三酰甘油的合成与储存[23]. 脂肪萎缩小鼠ASP缺乏, 餐后脂肪酸升高, 三酰甘油合成减少[17]. 提示补体C3是促进脂质沉积的起始因素, 其分解代谢产物促使脂肪细胞摄取脂质[24].
肝脏是脂质合成和代谢的主要器官, 脂质在脂肪细胞中以TG的形式储存. 当肝脏的脂质输入或生物合成远大于脂质氧化或输出时, 脂质在肝细胞内蓄积, 产生脂肪变性.
酒精性脂肪肝中乙醇可致磷酸甘油增多而促进三酰甘油的合成. 且乙醇在代谢过程中, 促进氧化型辅酶Ⅰ转变为还原型辅酶Ⅰ, 故使依赖于NADH的生化反应加强, 依赖NAD的反应如三羧酸循环、脂肪酸β氧化和氧化磷酸化、糖异生抑制. 患者出现高乳酸血症、高尿酸血症、低血糖、高脂血症、FLD等[25,26]. Pritchard等研究显示, 在用酒精喂养的天然小鼠血清中补体C3、C5均升高, 敲除C5基因小鼠与天然小鼠出现高TG血症, 而敲除C3基因小鼠没有出现高TG血症, 肝脏没有明显的脂质沉积, 提示补体C3促进肝细胞内脂质的沉积, 参与脂肪肝的发生与发展[4,9,27].
目前已证实脂肪肝存在氧化应激、脂质过氧化、线粒体功能失调、呼吸链复合物活性降低、活性氧簇(reactive oxygen species, ROS)及肿瘤坏死因子生成增加, 而TNF-α和脂质过氧化物使电子在呼吸链中传递氧的能力降低, 影响ATP的生成. 大量ROS使体内抗氧化剂耗竭, 导致体内氧自由基增多, 进一步形成恶性循环[3,28-29]. 肝脂肪变性时过多的脂肪细胞可分泌多种炎性因子, 导致肝细胞发生炎症浸润坏死, 甚至进展为肝纤维化及肝硬化. 炎症、坏死和凋亡激活补体, 补体又通过多种途径激发炎性反应, 导致肝脏促炎症(Th-1)和抗炎症(Th-2)细胞因子的失调[2,30]. 炎症反应也可降低脂肪组织缓冲(nonesterified fatty acids, NEFA)的能力, 尽管肥胖时机体的脂肪组织增加, 但血液中游离脂肪酸水平仍很高. 网膜释放出的NEFA通过门静脉沉积到肝脏内, 导致脂质产生增多[31,32].
补体促进各种炎性因子的激活. 有研究报道C5a、C5a desArg74、C4a、C4a desArg77结合其受体后, 无TG的合成[4]. Pritchard等研究报道用乙醇喂养后, 去除C5基因的小鼠血清中ALT与TNF-α不升高[4], 提示C5是重要的炎症介质, 与脂肪肝脂质沉积无相关性, 而与脂肪肝炎症反应的发生有关. 相关机制有(1)C5a是炎症反应的重要介质和趋化因子, 其受体广泛表达于肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞、中性粒细胞、单核巨噬细胞和内皮细胞等炎性细胞表面. C5a与相应受体结合, 可介导肥大细胞和单核细胞释放炎性介质[33]. (2)有研究报道C5a通过其受体-CD88和C5L2(C5a like receptor-2)来实现生物学活性[34,35]. C5a与CD88通过两点模型相互作用后, 介导一系列的炎症反应, 如激发细胞脱颗粒, 释放组胺, 增强血管通透性, 诱导白细胞表达分泌IL-6、TNF-α等细胞因子[36]. 有研究报道抗C5a单克隆抗体能够改善组织氧摄取并且降低IL-6和乳酸水平[37]. (3)C5a还能激活花生四烯酸代谢的脂氧合酶途径, 促进中性粒细胞和单核细胞进一步释放炎性介质. (4)补体C5对中性粒细胞有趋化作用, 并且抑制中性粒细胞凋亡[38], C5a可直接作用于血管内皮细胞, 导致血管渗透性增加并表达P-选择素, 促进中性粒细胞黏着于血管内皮细胞[39]. 并且中性粒细胞和单核细胞的趋化因子、中性粒细胞所释放的溶酶体及炎症渗出物中的蛋白水解酶又能激活补体[40], 从而形成驱动中性粒细胞游走的反馈性环路, 引起上述反应逐级发达, 继而引起肝细胞线粒体损伤, 脂蛋白形成减少[8,34,41], 减少脂质外运, 加重脂质在肝细胞内存积[42].
乙醇在小肠上段吸收的同时可使肠腔内毒素异位到门脉系统, 肝脏的库普弗细胞通过表达CD14或TLR诱发CD14表达, 促使其与异位内毒素成分脂多糖(LPS)结合, 并释放TNF-α激活一系列炎症反应. 内毒素是所有革兰阴性菌的细胞壁成分, 补体可清除内毒素. 有报道1993年, 英国Zenaide等对受脂多糖攻击的先天性C3缺陷狗进行观察, 提示补体C3可保护机体免受细菌毒素(内毒素)的损伤. 国内有实验证实, 通过静脉注射纯化人重组iC3b片段, 可以明显降低由大肠杆菌导致的小鼠内毒素休克的死亡率[43]. 提示补体参与了可以引发脂肪肝形成的内毒素的清除.
Th2辅助B细胞增殖, 产生抗体, 参与体液免疫应答. 其中C3处于三种补体激活途径的中间环节, 三途径最终形成C5转化酶, 裂解C5, 若此激活发生在脂质双层上, 则形成C5b-9, 即膜攻击复合物(MAC), 清除抗原抗体免疫复合物. TUNEL法检测发现NASH大鼠的肝细胞凋亡显著高于正常大鼠, 而且随着肝组织脂肪变、炎症和坏死的加重, 肝细胞的凋亡也越明显[44]. 因此, 补体可参与肝细胞坏死、凋亡细胞等自身抗原的清除.
FLD是代谢综合征的肝脏组分, 存在脂肪组织和肝脏等的天然免疫功能紊乱, 补体系统是获得性自身免疫系统的一部分, 脂肪因子和肝脏衍生的补体及致炎细胞因子与其受体结合, 使肝脏从脂质沉积发展到脂肪肝, 甚至脂肪性肝炎. 补体与脂肪肝关系的研究有助于我们对脂肪肝的发病机制进行更深入的认识, C5L2受体拮抗剂的研究有助于研发新一代治疗药物. 有必要深入了解补体在肝脏代谢性应激状态下的免疫机制, 从而进一步澄清其在FLD发生发展中的作用, 并采取措施预防病变发展.
脂肪肝(FLD)的发病机制尚未完全明确, 近来研究发现, FLD存在脂肪组织和肝脏等的天然免疫紊乱, 与补体密切相关, 来源于脂肪组织和肝脏的补体可能对FLD的发生发展起重要作用.
黄晓东, 副主任医师, 武汉市中心医院消化内科.
补体参与FLD疾病的发生发展, 但其具体作用机制错综复杂, 如何进一步澄清其作用机制并采取措施预防疾病发生、发展是当前亟待解决的问题.
英国Zenaide等对受脂多糖攻击的先天性C3缺陷狗进行观察, 提示补体C3可保护机体免受细菌毒素(内毒素)的损伤. 国内有实验证实, 通过静脉注射纯化人重组iC3b片段, 可以明显降低由大肠杆菌导致的小鼠内毒素休克的死亡率.
本文通过FLD早期预警因子进行测定, 提高对其早期诊断. 补体的分解产物ASP与受体C5L2结合后, 可促进脂肪细胞内三酰甘油的合成, 并调控肝脏成脂作用. 可通过阻断其作用受体进行更早期的干预治疗.
本文综述内容较为重要, 提供了有意义的信息.
编辑: 李军亮 电编: 何基才
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