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

Abstract

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.

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Fig. 1: C24 activates AMPK in HepG2 cells.
Fig. 2: The effects of C24 on lipogenesis in vitro and in vivo.
Fig. 3: C24 inhibits lipogenesis via AMPK pathway.
Fig. 4: Chronic C24 treatment improves lipid profiles in HC-fed New Zealand rabbits.
Fig. 5: C24 treatment improves dyslipidemia in HFHC-fed hamsters.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81673493, 81273566, and 81803596) and the National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology (2018ZX09711002).

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JYL, FJN, ZFX, and YMZ participated in the research design. SMS, ZFX, YMZ, XWZ, CDZ, YYY, and TTL performed the experiments and data analysis; JPY, YMZ, FJN, SCC, HWJ, and JL contributed new reagents and analytic tools; SMS, ZFX, JYL, and FJN contributed to the preparation of the paper.

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Correspondence to Fa-jun Nan or Jing-ya Li.

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Sun, S., Xie, Z., Zhang, Y. et al. AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-0472-9

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Keywords

  • adenosine 5′-monophosphate-activated protein kinase
  • AMPK activator
  • C24
  • liver
  • triglycerides
  • cholesterol
  • VLDL
  • hypolipidemic drug
  • metabolic syndrome