I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Cell Death Dis. 2013 Jul 4;4(7):e712. doi: 10.1038/cddis.2013.228.
The endemic occurrence of obesity and the associated risk factors that constitute the metabolic syndrome have been predicted to lead to a dramatic increase in chronic liver disease. Non-alcoholic steatohepatitis (NASH) has become the most frequent liver disease in countries with a high prevalence of obesity. In addition, hepatic steatosis and insulin resistance have been implicated in disease progression of other liver diseases, including chronic viral hepatitis and hepatocellular carcinoma. The molecular mechanisms underlying the link between insulin signaling and hepatocellular injury are only partly understood. We have explored the role of the antiapoptotic caspase-8 homolog cellular FLICE-inhibitory protein (cFLIP) on liver cell survival in a diabetic model with hypoinsulinemic diabetes in order to delineate the role of insulin signaling on hepatocellular survival. cFLIP regulates cellular injury from apoptosis signaling pathways, and loss of cFLIP was previously shown to promote injury from activated TNF and CD95/Apo-1 receptors. In mice lacking cFLIP in hepatocytes (flip(-/-)), loss of insulin following streptozotocin treatment resulted in caspase- and c-Jun N-terminal kinase (JNK)-dependent liver injury after 21 days. Substitution of insulin, inhibition of JNK using the SP600125 compound in vivo or genetic deletion of the mitogen-activated protein kinase (MAPK)9 (JNK2) in all tissues abolished the injurious effect. Strikingly, the difference in injury between wild-type and cFLIP-deficient mice occurred only in vivo and was accompanied by liver-infiltrating inflammatory cells with a trend toward increased amounts of NK1.1-positive cells and secretion of proinflammatory cytokines. Transfer of bone marrow from rag-1-deficient mice that are depleted from B and T lymphocytes prevented liver injury in flip(-/-) mice. These findings support a direct role of insulin on cellular survival by alternating the activation of injurious MAPK, caspases and the recruitment of inflammatory cells to the liver. Thus, increasing resistance to insulin signaling pathways in hepatocytes appears to be an important factor in the initiation and progression of chronic liver disease.
肥胖的地方性流行和构成代谢综合征的相关危险因素预计将导致慢性肝病的急剧增加。非酒精性脂肪性肝炎（NASH）已成为肥胖症高发国家最常见的肝病。此外，肝脂肪变性和胰岛素抵抗与其他肝病的疾病进展有关，包括慢性病毒性肝炎和肝细胞癌。胰岛素信号与肝细胞损伤之间的联系的分子机制仅部分被理解。我们已经研究了抗凋亡半胱天冬酶-8 同源物细胞 FLICE 抑制蛋白（cFLIP）在具有低胰岛素血症糖尿病的糖尿病模型中对肝细胞存活的作用，以便描绘胰岛素信号对肝细胞存活的作用。cFLIP 调节细胞损伤的凋亡信号通路，并且先前已经表明 cFLIP 的缺失会促进激活的 TNF 和 CD95/Apo-1 受体的损伤。在肝细胞中缺乏 cFLIP 的小鼠（flip(-/-)）中，链脲佐菌素处理后胰岛素的丧失导致 caspase 和 c-Jun N 末端激酶（JNK）依赖性肝损伤 21 天后。用 SP600125 化合物体内抑制 JNK 或在所有组织中遗传缺失丝裂原活化蛋白激酶（MAPK）9（JNK2）取代胰岛素消除了损伤作用。引人注目的是，野生型和 cFLIP 缺陷型小鼠之间的损伤差异仅在体内发生，并伴有肝浸润的炎性细胞，具有增加 NK1.1 阳性细胞数量和分泌促炎细胞因子的趋势。来自 B 和 T 淋巴细胞耗竭的 rag-1 缺陷型小鼠的骨髓转移可防止 flip(-/-)小鼠的肝损伤。这些发现支持胰岛素通过改变有害的 MAPK、半胱天冬酶和炎性细胞募集到肝脏的激活对细胞存活的直接作用。因此，增加肝细胞中胰岛素信号通路的抗性似乎是慢性肝病起始和进展的重要因素。
