Aim To explore the effect of proline/serine rich coiled coil protein 1-mediated long non-coding RNA (lncLEPIS) overexpression on blood lipid levels and the occurrence and development of atherosclerosis. Methods 16 ApoE－/－ mice were randomly divided into control group (NC group) and lncLEPIS overexpression group (lncLEPIS group), and ApoE－/－ mice fed with high-fat diet with liver lncLEPIS overexpression were constructed. Atherosclerotic plaques in mouse aorta were assessed by oil red O staining. Blood lipid levels were detected by enzyme labeling method.The mRNA expression levels of cholesterol metabolism-related genes were detected by real-time quantitative PCR. Results The plaque area/aortic area in the NC group and the lncLEPIS group were (18.6%±0.3%) and (28.0%±1.3%), and the plaque area/aortic root cross-sectional area were (7.5%±0.2%) and (17.8%±0.3%), the differences between the two groups was significant (P＜0.05). The plasma triglyceride levels of the mice in the NC group and the lncLEPIS group were (0.65±0.07) mmol/L and (0.96±0.21) mmol/L, the total cholesterol levels were (3.56±0.71) mmol/L and (7.36±0.65) mmol/L, the high density lipoprotein cholesterol levels were (1.46±0.05) mmol/L and (1.95±0.38) mmol/L, and the low density lipoprotein cholesterol levels were (2.59±0.35) mmol/L and (5.59±0.59) mmol/L, the differences between the two groups were significant (P＜0.05). Compared with the NC group, the expression level of low density lipoprotein receptor (LDLR) in the liver of mice was down-regulated by 48.4% in the lncLEPIS group, and the expression level of proprotein convertase subtilisin/kexin 9 (PCSK9) was up-regulated by 62.8% (P＜0.05). Conclusion Overexpression of lncLEPIS reduces the expression of LDLR, promotes the expression of PCSK9, increases the level of plasma LDLC, and promotes the occurrence and development of atherosclerosis.