Berberine, as alkaloid isolated from the Chinese herbs, is reported to have a lipid lowering effect by up-regulating hepatic low density lipoprotein receptor (LDLR). In this study, we investigated the effect of berberine on serum lipid level and atherosclerosis other than LDLR receptor up-regulation using the genetically modified animal model. We treated the berberine (10mg/kg/day) or equal volume of vehicle (0.9% saline) in three different mouse models (LDLR-/-, LDLR+/-, and wild type) for 8 weeks with western diet. The total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels are checked at the beginning of experiment, 4 weeks, and 8 weeks. At the end of experiment, the heart was fixed and the lipid accumulation in aortic valve lesion was evaluated. There was no significant change of total cholesterol level with berberine treatment in wild type. Unexpectedly, berberine treatment significantly increased serum total cholesterol level (286.9짹50.1 mg/dL at baseline and 2527.5짹814.6 mg/dL at 8 weeks) compared to vehicle (303.7짹45.6 mg/dL at baseline and 831.3짹829.6 mg/dL at 8 weeks) (p<0.001) in LDLR-/- group. In LDLR+/- group, mild elevation of cholesterol was observed in both berberine and vehicle treated group. Berberine treatment increased the HDL cholesterol level in LDLR-/- and LDLR+/- group, but not in wild group. Significant lipid accumulations were observed only in LDLR-/- group with 8 weeks western diet. Interestingly, berberine treatment did not increase the lipid accumulation in aortic valve even with higher cholesterol level compared to vehicle treated group. In conclusion, we observed berberine treatment worsened the lipid profile in a model of abnormal LDLR function and this suggests lipid lowing effect of berberine is modulated by the LDLR expression. Further evaluations are needed to clarify the mechanism and to identify whether similar effect occurs in human before developing it as a lipid lowering agent.