TNFR1 controls apoptosis and chronic liver disease in hepatocyte-specific IKKγ (Nemo) mice.. Mus musculus

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-ĸB essential modulator in hepatocytes (NemoΔhepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in NemoΔhepa mice. Therefore, we generated NemoΔhepa/TRAIL-/- and NemoΔhepa/TNFR1-/- animals and analyzed the progression of liver injury. NemoΔhepa/TRAIL-/- displayed a similar phenotype to NemoΔhepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in NemoΔhepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in NemoΔhepa and NemoΔhepa/TRAIL-/- mice while NemoΔhepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in NemoΔhepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice. Overall design: Expression profiling of livers from wild type, NEMO, NEMO-TRIAL, and NEMO-TNFR null mice

死亡受体介导的肝细胞凋亡广泛参与多种肝脏疾病的发生发展，涵盖病毒性肝炎、酒精性肝炎、缺血/再灌注损伤、暴发性肝衰竭、胆汁淤积性肝损伤及肝癌。在小鼠肝细胞中敲除NF-κB必需调节蛋白（NemoΔhepa），可诱导小鼠先出现脂肪性肝炎，随后自发形成肝细胞癌，因此该模型是研究从慢性肝炎进展为肝癌的理想动物模型。本研究旨在解析NemoΔhepa小鼠中介导肝损伤的死亡受体通路。为此，我们构建了NemoΔhepa/TRAIL-/-与NemoΔhepa/TNFR1-/-基因工程小鼠，并分析其肝损伤进展情况。NemoΔhepa/TRAIL-/-小鼠呈现出与NemoΔhepa小鼠相似的表型，特征为高水平细胞凋亡、免疫细胞浸润、肝细胞增殖及脂肪性肝炎。而NemoΔhepa/TNFR1-/-小鼠的肝脏中，上述病理生理特征得到显著改善。NemoΔhepa与NemoΔhepa/TRAIL-/-小鼠的肝细胞凋亡水平升高；而NemoΔhepa/TNFR1-/-小鼠的细胞死亡程度降低，同时伴随pJNK（磷酸化c-Jun氨基末端激酶）水平显著下降。NemoΔhepa/TNFR1-/-小鼠肝脏中的细胞周期相关指标激活程度显著降低。此外，该组小鼠的肝纤维化标志物与肿瘤进展相关指标均显著下调。本研究数据表明，死亡受体TNFR1（肿瘤坏死因子受体1）而非TRAIL（肿瘤坏死因子相关凋亡诱导配体）是调控肝细胞特异性Nemo敲除小鼠肝损伤进展的关键因子。实验整体设计：对野生型、NEMO单敲除、NEMO-TRAIL双敲除以及NEMO-TNFR全敲除小鼠的肝脏进行表达谱分析。