Abstract: OBJECTIVE To study the intervention effect of neferine on non-alcoholic fatty liver disease in ApoE^-/- mice and its molecular mechanism. METHODS Ten C57BL/6 mice were used as normal control group, and 50 ApoE^-/- mice were randomly divided into model group, compound methionine acetylcholine solution group(0.4 g·kg^-1·d^-1), neferine high dose group(8.0 mg·kg^-1·d^-1) and low dose group(4.0 mg·kg^-1·d^-1), 10 in each group. Except the normal control group, other groups of mice were given high-fat diet. Liver tissue morphology was observed by HE and oil red O staining. Ultrastructural changes of hepatocytes were observed by transmission electron microscopy. The levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in serum, the activities of superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px), and the contents of malondialdehyde(MDA), total cholesterol(TC) and triglyceride(TG) in liver were determined. In addition, the level of liver X receptor α(LXR-α) protein and the mRNA expression of its downstream target genes were measured, such as cholesterol regulatory element binding protein 1c(SREBP-1c), fatty acid synthase(FAS), acetyl-coenzyme A carboxylase(ACC1) and stearoyl coenzyme A desaturase-1(SCD-1). RESULTS Pathological staining showed that neferine could significantly inhibit liver steatosis, reduce serum ALT and AST levels, MDA and lipid levels in liver(P < 0.05), and increase liver SOD and GSH-Px activities. In addition, neferine could significantly inhibit the expression of LXR-α and its downstream target genes(P < 0.05). CONCLUSION Neferine can effectively interfere with hepatic steatosis in ApoE^-/- mice, and its mechanism may be related to the reduction of oxidative stress, inhibition of LXR-α expression and transcriptional activity.