Rensen Sander S, Slaats Yanti, Driessen Ann, Peutz-Kootstra Carine J, Nijhuis Jeroen, Steffensen Rudi, Greve Jan Willem, Buurman Wim A
Department of Surgery, NUTRIM School for Nutrition, Toxicolgy, and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
Hepatology. 2009 Dec;50(6):1809-17. doi: 10.1002/hep.23228.
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), C4d, 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 C4d. 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-1beta expression. Moreover, nonalcoholic steatohepatitis (NASH) was more prevalent in patients showing hepatic C9 or activated C3 deposition.
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.
固有免疫系统的激活在非酒精性脂肪性肝病（NAFLD）中起主要作用。补体系统是固有免疫的重要组成部分，可识别诸如组织损伤等危险信号。我们旨在确定补体系统激活是否在NAFLD中发生，识别起始途径，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分析，检测补体因子C1q、甘露糖结合凝集素（MBL）、C4d、活化的C3和膜攻击复合物（MAC）相关的C9的沉积情况。此外，对肝中性粒细胞浸润、细胞凋亡和促炎细胞因子表达进行定量分析。健康受试者肝脏中未检测到补体激活，而74%的NAFLD患者肝脏出现活化C3和C4d沉积。在大多数活化C3阳性患者中发现C1q以及MBL积聚。引人注目的是，50%的活化C3阳性患者还表现出MAC相关的C9沉积。补体因子沉积主要见于大泡性脂肪变性的肝细胞周围。显示活化C3积聚的受试者凋亡细胞数量增加。重要的是，在显示活化C3沉积的患者中，肝中性粒细胞浸润以及白细胞介素（IL）-8和IL-6表达显著更高，而C9沉积的患者IL-1β表达进一步增加。此外，在肝脏出现C9或活化C3沉积的患者中，非酒精性脂肪性肝炎（NASH）更为普遍。
NAFLD中存在补体系统的广泛激活，这与疾病严重程度相关。鉴于补体因子在凋亡细胞清除、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。
