Objective: To investigate the effect of sodium valproate on mice model of non-alcoholic fatty liver disease (NAFLD) induced by high-fat and high-cholesterol diet. Methods: Forty-two male C57BL/6J mice aged 7-8 weeks were randomly divided as the control group, the model group, and the intervention group. The control group was fed with standard diet, and the model group and the intervention group were fed with high-fat and high-cholesterol diet. Eight weeks after initiation of the experimental diets, the intervention group was given sodium valproate (drinking water with 0.4% sodium valproate) for 8 weeks, while the control group and the model group were given the regular drinking water. Mice were sacrificed after the experiment. The body weight, liver index, serum biochemical indexes, liver histopathological changes, and the relationship with prolyl endopeptidase (PREP) were observed in all mice. Results: Compared with the control group, the body weight, liver index and
epididymal fat index of the model group were significantly increased (P<0.05). Compared with the model group,the intervention group had statistically decreased liver index (P<0.05), but there was no significant difference in body weight or epididymal fat index between the two groups (P>0.05). Serum total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), alanine aminotransferase (ALT), alkaline phosphatase (ALP), fasting blood glucose (FBG), and fasting insulin (Insulin) in the model group were significantly higher than those of the control group (P<0.05); compared with the model group, TC, TG and ALT in the intervention group were significantly decreased (P<0.05), while there was no statistical difference in LDL, AST, ALP, FBG, and Insulin between the two groups (P>0.05). The liver tissue in the model group showed obvious steatosis, inflammation and ballooning.After intervention with sodium valproate, steatosis and inflammation were markedly attenuated, and NAFLD activity score (NAS) was significantly decreased (P<0.05). In liver tissue of the model group, the RQ value of PREP mRNA was (2.02±0.13) and the protein activity of PREP was (473.39±15.41) pmol·mg-1·min-1, both higher than those in the control group (P<0.05). In liver tissue of the intervention group, the RQ value of PREP mRNA was (1.86±0.18), showing no significant difference from that of the model group (P>0.05); however, the protein activity of PREP in the intervention group was (397.41±9.63) pmol·mg-1·min-1, significantly lower than that in the model group (P<0.05). There was no statistical difference in the PREP protein level in liver tissues of three groups (P>0.05). Conclusion: Sodium valproate can attenuate liver steatosis and inflammation in NAFLD mice model by inhibiting PREP activity.