Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma.Recently,various studies demonstrate that the increased activity of adenosine 5'-monophosphate-activated protein kinase(AMPK)causes health benefits in energy regulation.Thus,great efforts have been made to develop AMPK activators as a metabolic syndrome treatment.In the present study,we investigated the effects of the AMPK activator C24 on dyslipidemia and the potential mechanisms.We showed that C24(5-40 μM)dose-dependently increased the phosphorylation of AMPKα and acetyl-CoA carboxylase(ACC),and inhibited lipogenesis in HepG2 cells.Using compound C,an AMPK inhibitor,or hepatocytes isolated from liver tissue-specific AMPK knockout AMPKα1α2fl/fl;Alb-cre mice(AMPK LKO),we demonstrated that the lipogenesis inhibition of C24 was dependent on hepatic AMPK activation.In rabbits with high-fat and high-cholesterol diet-induced dyslipidemia,administration of C24(20,40,and 60 mg·kg-1.d-1,ig,for 4 weeks)dose-dependently decreased the content of TG,total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)in plasma and played a role in protecting against hepatic dysfunction by decreasing lipid accumulation.A lipid-lowering effect was also observed in high-fat and high-cholesterol diet-fed hamsters.In conclusion,our results demonstrate that the small molecular AMPK activator C24 alleviates hyperlipidemia and represents a promising compound for the development of a lipid-lowering drug.