Article

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

Authors: Shui-mei Sun1,2, Zhi-fu Xie1, Yang-ming Zhang1,2,3, Xin-wen Zhang1, Chen-dong Zhou1, Jian-peng Yin3, Yan-yan Yu1, Shi-chao Cui1, Hao-wen Jiang1, Teng-teng Li1,2,4, Jia Li1,2,4, Fa-jun Nan1,2,3, Jing-ya Li1,2
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Correspondence to: Fa-jun Nan: fjnan@simm.ac.cn, Jing-ya Li: jyli@simm.ac.cn,
DOI: 10.1038/s41401-020-0472-9
Received: 6 March 2020
Accepted: 3 July 2020
Advance online: 28 July 2020

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.
Keywords: adenosine 5′-monophosphate-activated protein kinase; AMPK activator; C24; liver; triglycerides; cholesterol; VLDL; hypolipidemic drug; metabolic syndrome

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