Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages
Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages
复制标题
Scoparone 通过调节巨噬细胞中 ROS/P38/Nrf2 轴和 PI3K/AKT/mTOR 通路改善非酒精性脂肪性肝炎小鼠的肝脏炎症和自噬
DOI：
10.1016/j.biopha.2020.109895
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发表时间：
2020-05-01
影响因子：
7.5
通讯作者：
Xu, Keshu
中科院分区：
文献类型：
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作者：
Liu, Beibei;Deng, Xiaoling;Xu, Keshu
背景和目标：滨蒿内酯已被证明可以改善许多形式的肝脏疾病，并且先前已经揭示了涉及的几种潜在分子机制。然而，滨蒿内酯在非酒精性脂肪性肝病-非酒精性脂肪性肝炎（NAFLD-NASH）中失调的自噬中的潜在作用尚未得到评估。在目前的研究中，我们研究了滨蒿内酯在NASH.Methods小鼠肝脏自噬的影响和潜在的机制：在体内，小鼠喂养蛋氨酸胆碱缺乏（MCD）的饮食，建立NASH模型，然后进行治疗或不滨蒿内酯4周。在体外，滨蒿内酯应用于肝细胞脂质过负荷模型中的AML 12细胞与棕榈酸（PA）的挑战和脂多糖（LPS）诱导的RAW264.7 cells.Results：滨蒿内酯改善受损的自噬和几个关键特征的NASH小鼠喂食MCD饮食。在体外，滨蒿内酯对巨噬细胞的自噬有影响，但对肝细胞无影响。在RAW264.7细胞中，滨蒿内酯减少LPS诱导的自噬体和自噬底物的积累，活性氧（ROS）的产生和炎症反应。滨蒿内酯可抑制ROS/P38/Nrf 2轴介导的p62转录上调。氯喹（CQ），自噬通量的抑制剂，显着抑制滨蒿内酯介导的炎症保护作用。此外，滨蒿内酯抑制PI 3 K/AKT/mTOR通路的激活，MHY 1485（一种抑制自噬的mTOR激活剂）抑制滨蒿内酯的抗炎作用。结论：在LPS诱导的巨噬细胞中，滨蒿内酯通过抑制ROS/P38/Nrf 2轴和PI 3 K/AKT/mTOR通路，增强自噬通量，调节自噬，进而抑制炎症反应。滨蒿内酯可能部分通过增强巨噬细胞的自噬作用而不是肝细胞的自噬作用来改善肝脏自噬和NASH。滨蒿内酯有望成为NASH或与巨噬细胞自噬失调相关疾病的新型治疗药物。
Background and aims: Scoparone has been shown to ameliorate many forms of liver disease, and several underlying molecular mechanisms involved have been previously revealed. However, the potential role of scoparone in autophagy, which is dysregulated in nonalcoholic fatty liver disease-nonalcoholic steatohepatitis (NAFLD-NASH), has not been evaluated. In the current study, we investigated the effect and potential mechanisms of scoparone in hepatic autophagy in mice with NASH.Methods: In vivo, mice were fed a methionine-choline deficient (MCD) diet to establish a NASH model and then subjected to treatment with or without scoparone for 4 weeks. In vitro, scoparone was applied in a hepatocellular lipid overload model in AML12 cells challenged with palmitic acid (PA) and in lipopolysaccharide (LPS)-induced RAW264.7 cells.Results: Scoparone improved impaired autophagy and several key features of NASH in mice fed an MCD diet. In vitro, scoparone had an effect on the autophagy of macrophages but not hepatocytes. In RAW264.7 cells, scoparone reduced the LPS-induced accumulation of autophagosomes and autophagy substrates, the production of reactive oxygen species (ROS) and the inflammatory response. Scoparone inhibited the upregulation of p62 transcription, which is mediated by the ROS/P38/Nrf2 axis. Chloroquine (CQ), an inhibitor of autophagic flux, significantly inhibited scoparone-mediated protection against inflammation. In addition, scoparone suppressed activation of the PI3K/AKT/mTOR pathway, and MHY1485 (an mTOR activator that inhibits autophagy) inhibited the anti-inflammatory effect of scoparone.Conclusions: In LPS-induced macrophages, scoparone regulates autophagy and further suppresses inflammation by inhibiting the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway and enhancing autophagic flux. Scoparone may improve hepatic autophagy and NASH partly through enhancing autophagy in macrophages but not hepatocytes. Scoparone is expected to become a novel therapeutic drug for NASH or diseases associated with dysregulated autophagy in macrophages.