A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism

doi:10.1016/j.ejps.2020.105683

	A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism
	Huang, Jun-Shang 1,2; Guo, Bin-Bin 2; Lin, Fei-Fei 2; Zeng, Li-Min 2; Wang, Ting 2; Dang, Xiang-Yu 2; Yang, Yang 1,2; Hu, You-Hong 1,2; Liu, Jia 2; Wang, He-Yao 1,2
刊名	EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
	2021-03-01
卷号	158 页码:9
关键词	DGAT1 Inhibitor Pharmacokinetics Dyslipidemia Lipid metabolism
ISSN号	0928-0987
DOI	10.1016/j.ejps.2020.105683
通讯作者	Hu, You-Hong(yhhu@simm.ac.cn) ; Liu, Jia(jia.liu@simm.ac.cn) ; Wang, He-Yao(hywang@simm.ac.cn)
英文摘要	Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC50 = 18.24 +/- 4.72 nM) than LCQ908 (IC50 = 78.24 +/- 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liverand intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.
资助项目	National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-002-007] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040336] ; National Natural Science Foundation of China[81773791] ; National Natural Science Foundation of China[81473262] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120162025]
WOS关键词	CARBOXYLIC-ACID DERIVATIVES ; TRIGLYCERIDE SYNTHESIS ; POTENTIAL TREATMENT ; DGAT1 INHIBITORS ; OBESITY ; DISCOVERY ; FAT ; LIPOPROTEINS ; STEATOSIS ; SECRETION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000613276200004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295857]
专题	中国科学院上海药物研究所
通讯作者	Hu, You-Hong; Liu, Jia; Wang, He-Yao
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Huang, Jun-Shang,Guo, Bin-Bin,Lin, Fei-Fei,et al. A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism[J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,2021,158:9.
APA	Huang, Jun-Shang.,Guo, Bin-Bin.,Lin, Fei-Fei.,Zeng, Li-Min.,Wang, Ting.,...&Wang, He-Yao.(2021).A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,158,9.
MLA	Huang, Jun-Shang,et al."A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism".EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 158(2021):9.