AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models

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 mu M) dose-dependently increased the phosphorylation of AMPK alpha 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 AMPK alpha 1 alpha 2(fl/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 center dot kg(-1)center dot 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.

Automated summary

The AMPK activator C24 shows promise in alleviating dyslipidemia by activating hepatic AMPK, reducing lipogenesis, lowering lipid levels in plasma, and protecting against hepatic dysfunction. C24 may be a potential candidate for the development of a lipid-lowering drug.