AbstractAimWe investigated whether transient receptor potential vanilloid type 1 (TRPV1) was involved in the therapeutic effect of evodiamine, a main bioactive component in the fruit of Evodiae rutaecarpa, on the development of atherosclerosis in apolipoprotein E‐deficient (ApoE−/−) mice and ApoE−/−TRPV1−/− mice.MethodsHistopathology was examined by haematoxylin and eosin staining, levels of cytokines and mediators were evaluated by ELISA kits, and protein expression was determined by Western blotting.ResultsChronic administration with evodiamine (10 mg kg−1 body weight) reduced the size of atherosclerotic lesions and alleviated the hyperlipidaemia and systemic inflammation, as well as hepatic macrovesicular steatosis, in ApoE−/− mice. Treating ApoE−/− mice with evodiamine enhanced hepatic cholesterol clearance, as revealed by upregulation of hepatic low‐density lipoprotein receptor and ATP‐binding cassette (ABC) transporters ABCG5, ABCG8 and cholesterol 7α‐hydrolase. Genetic deletion of TRPV1 in ApoE−/− mice promoted the progression of atherosclerosis; elevated the serum levels of cholesterol, cytokines and chemokines; and exacerbated hepatic macrovesicular steatosis. Moreover, genetic deletion of TRPV1 abrogated the evodiamine‐evoked atheroprotection but not anti‐obesity effect in ApoE−/− mice.ConclusionEvodiamine may confer novel TRPV1‐dependent atheroprotection and TRPV1‐independent anti‐obesity action.