脂肪性肝炎
脂毒性
肝细胞
纤维化
旁分泌信号
脂肪肝
脂肪变性
非酒精性脂肪肝
胰岛素抵抗
细胞生物学
肝星状细胞
生物
自分泌信号
炎症
脂质代谢
内科学
脂滴
内分泌学
化学
胰岛素
β氧化
癌症研究
胰岛素受体
医学
生物化学
疾病
体外
受体
作者
Jinrui Dong,Sivakumar Viswanathan,Eleonora Adami,Brijesh K. Singh,Sonia Chothani,Benjamin Ng,W. Lim,Jin Zhou,Madhulika Tripathi,Nicole S. J. Ko,Shamini Guna Shekeran,Jessie Tan,Sze Yun Lim,Mao Wang,Pei Min Lio,Paul M. Yen,Sebastian Schafer,Stuart A. Cook,Anissa A. Widjaja
标识
DOI:10.1038/s41467-020-20303-z
摘要
IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition. IL11 contributes to the development of non-alcoholic steatohepatitis (NASH) through incompletely understood mechanisms. Here, the authors report that lipotoxicity-driven autocrine IL11 activity underlies hepatocyte metabolic dysfunction and death via a NOX4/ERK-mediated mechanism while paracrine IL11 activity stimulates hepatic stellate cells contributing to fibrosis and inflammation in the context of NASH.
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