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 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. 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. 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. 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.