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

doi:10.1038/s41401-020-0472-9

	AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models
	Sun, Shui-mei 1,2; Xie, Zhi-fu 1; Zhang, Yang-ming 1,2,3; Zhang, Xin-wen 1; Zhou, Chen-dong 1; Yin, Jian-peng 3; Yu, Yan-yan 1; Cui, Shi-chao 1; Jiang, Hao-wen 1; Li, Teng-teng 1,2,4
刊名	ACTA PHARMACOLOGICA SINICA
	2020-07-28
页码	8
关键词	adenosine 5 '-monophosphate-activated protein kinase AMPK activator C24 liver triglycerides cholesterol VLDL hypolipidemic drug metabolic syndrome
ISSN号	1671-4083
DOI	10.1038/s41401-020-0472-9
通讯作者	Nan, Fa-jun(fjnan@simm.ac.cn) ; Li, Jing-ya(jyli@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81673493] ; National Natural Science Foundation of China[81273566] ; National Natural Science Foundation of China[81803596] ; National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology[2018ZX09711002]
WOS关键词	PROTEIN-KINASE CASCADE ; FATTY-ACID ; CHOLESTEROL-SYNTHESIS ; ATHEROSCLEROSIS ; HOMEOSTASIS ; INSULIN ; METABOLISM ; LIVER ; STEATOSIS ; TARGETS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000553293400003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292215]
专题	中国科学院上海药物研究所
通讯作者	Nan, Fa-jun; Li, Jing-ya
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Yantai Inst Mat Med, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Sun, Shui-mei,Xie, Zhi-fu,Zhang, Yang-ming,et al. AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models[J]. ACTA PHARMACOLOGICA SINICA,2020:8.
APA	Sun, Shui-mei.,Xie, Zhi-fu.,Zhang, Yang-ming.,Zhang, Xin-wen.,Zhou, Chen-dong.,...&Li, Jing-ya.(2020).AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models.ACTA PHARMACOLOGICA SINICA,8.
MLA	Sun, Shui-mei,et al."AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models".ACTA PHARMACOLOGICA SINICA (2020):8.