Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the liver stroma is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes 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. 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. The Ribo-seq and RNA-seq .bam files in this submission include alignment reads for IL11R, IL6R and GP130 as presented in the publication.

白细胞介素11（IL11）在非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）相关纤维化进程中发挥关键作用，但其在肝基质之外的功能尚不明确。本研究探讨了IL11在肝细胞脂毒性中的作用。肝细胞可表达IL11受体α（IL11RA），并在脂质负荷刺激下分泌IL11。自分泌IL11信号可通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）介导的活性氧（reactive oxygen species, ROS）产生、细胞外调节蛋白激酶（extracellular regulated protein kinases, ERK）与c-Jun氨基末端激酶（c-Jun N-terminal kinase, JNK）的激活及半胱天冬酶-3（caspase-3）的活化，引发肝细胞死亡，同时伴随线粒体功能受损与脂肪酸氧化能力降低。旁分泌IL11信号则可激活肝星状细胞，进而诱导纤维化。在NASH小鼠模型中，肝细胞特异性敲除Il11ra1可减轻肝脏脂肪变性、纤维化与炎症反应，同时降低血清葡萄糖、胆固醇与甘油三酯水平，并限制体重增加。在Il11ra1敲除小鼠中，恢复肝细胞内的IL11顺式信号通路可重新诱导脂肪变性与炎症反应。本研究未发现肝细胞或NASH模型中存在白细胞介素6（IL6）或IL11反式信号通路的相关证据。上述结果表明，IL11可调控肝细胞代谢，并为非酒精性脂肪肝（non-alcoholic fatty liver disease, NAFLD）向NASH的转化提供了潜在机制。本提交的核糖体测序（Ribo-seq）与RNA测序（RNA-seq）BAM格式文件包含了本研究论文中提及的IL11R、IL6R与糖蛋白130（GP130）的比对读数。