［Abstract］ Objective: This study aims to investigate the role of sphingosine-1-phosphate receptor 2 (S1PR2), proprotein convertase subtilisin/kexin type9（PCSK9）in nonalcoholic steatohepatitis（NASH）. Methods：Sixteen C57BL/6J mice were randomly assigned to control group and methionine choline deficiency diet (MCD) group. After NASH models were successfully established by MCD diet for six weeks, serum and liver biochemical indices(ALT, AST, GGT) and inflammatory factors (TNF -α, IL-6, IFN- γ) were detected by ELISA．HE staining, oil red O staining and sirius red staining were used to observe liver inflammatory damage, lipid deposition and fibrosis. In vitro, the primary hepatocytes of C57BL/6J mice and HepG2 cells were challenged with palmitic acid (PA), and/or JTE-013 (S1PR2 specific inhibitor) respectively; the lipid deposition was observed by oil red O staining, and the protein expression of S1PR2、PCSK9 and low?density lipoprotein cholesterol receptor (LDLR) was detected by Western blot. HepG2 cells were transfected with S1PR2 interference or overexpression plasmids to find potential related genes by gene chip technology, and genes with significant expression differences were screened out in NASH mice. Results: Compared with the placebo group, expression level of liver S1PR2 was decreased and PCSK9 increased. In mouse primary hepatocytes and HepG2 cells, JTE-013 could increase lipid deposition, and increase the expression of phosphorylated ERK and PCSK9, while the expression of LDLR was decreased. A total of 343 genes were changed in HepG2 cells transfected with S1PR2 knockdown and overexpression plasmids. The levels of early growth response protein 1 (Egr1) increased when S1PR2 was overexpressed and decreased when S1PR2 was interfered, and decreased in NASH model mice. Conclusion: S1PR2 is involved in the lipid metabolism and inflammatory injury of NASH, which may be related to the suppression of S1PR2 in inflammatory state, which further increase the expression of PCSK9 and decrease the expression of LDLR.