Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
Nat Commun. 2021 Jan 4;12(1):66. doi: 10.1038/s41467-020-20303-z.
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 在非酒精性脂肪性肝炎（NASH）纤维化中很重要，但它在肝脏疾病中超出基质的作用尚不清楚。在这里，我们研究了 IL11 在肝细胞脂肪毒性中的作用。肝细胞高度表达 IL11RA，并在脂质负荷下分泌 IL11。自分泌 IL11 活性通过 NOX4 衍生的 ROS、ERK、JNK 和 caspase-3 的激活、线粒体功能受损和脂肪酸氧化减少导致肝细胞死亡。旁分泌 IL11 活性刺激肝星状细胞并导致纤维化。在 NASH 的小鼠模型中，肝细胞特异性缺失 Il11ra1 可防止肝脂肪变性、纤维化和炎症，同时降低血清葡萄糖、胆固醇和甘油三酯水平并限制肥胖。在 Il11ra1 缺失的小鼠中，恢复肝细胞中的 IL11 顺式信号重新构成脂肪变性和炎症，但不构成纤维化。我们没有发现肝细胞或 NASH 中存在 IL6 或 IL11 转信号的证据。这些数据表明 IL11 调节肝细胞代谢，并提示 NAFLD 向 NASH 转化的机制。
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