Activation of the Complement System in Human Nonalcoholic Fatty Liver Disease
Activation of the Complement System in Human Nonalcoholic Fatty Liver Disease
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DOI：
10.1002/hep.23228
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发表时间：
2009-12-01
期刊：
影响因子：
13.5
通讯作者：
Buurman, Wim A.
中科院分区：
文献类型：
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作者：
Rensen, Sander S.;Slaats, Yanti;Buurman, Wim A.
先天免疫系统的激活在非酒精性脂肪肝（NAFLD）中起着重要作用。补体系统是先天免疫的一个重要组成部分，可以识别危险信号，如组织损伤。我们的目的是确定补体系统的激活是否发生在NAFLD中，以确定启动途径，并评估补体激活，NAFLD严重程度，细胞凋亡和炎症参数之间的关系。对43例患有不同程度NAFLD的肥胖受试者和10例健康对照者的肝活检组织进行补体因子C1 q、甘露糖结合凝集素（MBL）、Cod、活化C3和膜攻击复合物（MAC）相关C9沉积分析。此外，定量肝中性粒细胞浸润、细胞凋亡和促炎细胞因子表达。尽管在健康受试者的肝脏中检测不到补体活化，但74%的NAFLD患者显示活化的C3和Cod的肝脏沉积。在大多数激活的C3阳性患者中发现了C1 q和MBL积聚。引人注目的是，50%的活化C3阳性患者也显示MAC相关的C9沉积。补体因子沉积主要见于大泡性脂肪变性肝细胞周围。显示活化C3蓄积的受试者显示凋亡细胞数量增加。重要的是，肝中性粒细胞浸润以及白细胞介素（IL）-8和IL-6表达在显示活化C3沉积的患者中显著较高，而C9沉积的患者另外具有增加的IL-1 β表达。此外，非酒精性脂肪性肝炎（NASH）在显示肝脏C9或活化C3沉积的患者中更常见。结论：NAFLD患者存在广泛的补体系统激活，并与疾病严重程度相关。鉴于补体因子在清除凋亡细胞、肝纤维化和肝再生中的作用，这可能对NAFLD的发病机制和进展具有重要意义。（《肝脏病学》2009年;50：1809-1817）
Activation of the innate immune system plays a major role in nonalcoholic fatty liver disease (NAFLD). The complement system is an important component of innate immunity that recognizes danger signals such as tissue injury. We aimed to determine whether activation of the complement system occurs in NAFLD, to identify initiating pathways, and to assess the relation between complement activation, NAFLD severity, apoptosis, and inflammatory parameters. Liver biopsies of 43 obese subjects with various degrees of NAFLD and of 10 healthy controls were analyzed for deposition of complement factors C1q, mannose-binding lectin (MBL), Cod, activated C3, and membrane attack complex (MAC)-associated C9. Furthermore, hepatic neutrophil infiltration, apoptosis, and pro-inflammatory cytokine expression were quantified. Whereas complement activation was undetectable in the liver of healthy subjects, 74% of the NAFLD patients showed hepatic deposition of activated C3 and Cod. C1q as well as MBL accumulation was found in most activated C3-positive patients. Strikingly, 50% of activated C3-positive patients also displayed MAC-associated C9 deposition. Deposition of complement factors was predominantly seen around hepatocytes with macrovesicular steatosis. Subjects showing accumulation of activated C3 displayed increased numbers of apoptotic cells. Importantly, hepatic neutrophil infiltration as well as interleukin (IL)-8 and IL-6 expression was significantly higher in patients showing activated C3 deposition, whereas patients with C9 deposition additionally had increased IL-1 beta expression. Moreover, nonalcoholic steatohepatitis (NASH) was more prevalent in patients showing hepatic C9 or activated C3 deposition. Conclusion: There is widespread activation of the complement system in NAFLD, which is associated with disease severity. This may have important implications for the pathogenesis and progression of NAFLD given the function of complement factors in clearance of apoptotic cells, hepatic fibrosis, and liver regeneration. (HEPATOLOGY 2009;50:1809-1817.)