E3317 promotes cholesterol efflux in macrophage cells via enhancing ABCA1 expression.
E3317 promotes cholesterol efflux in macrophage cells via enhancing ABCA1 expression.
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E3317 通过增强 ABCA1 表达促进巨噬细胞中的胆固醇流出。
DOI：
10.1016/j.bbrc.2018.08.125
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Si Shuyi
中科院分区：
文献类型：
--
作者：
Wang Xiao;Luo Jinque;Li Ni;Liu Lunming;Han Xiaowan;Liu Chao;Zuo Xuan;Jiang Xinhai;Li Yining;Xu Yanni;Si Shuyi
Reverse cholesterol transport (RCT) plays an important role in cholesterol and lipid metabolism. Regulating the activities of key transporters and receptors in RCT, such as ATP-binding cassette transporter A1 (ABCA1), helps to prevent atherosclerotic cardiovascular disease. In this study, we used an ABCA1 promoter luciferase reporter assay to screen 20,000 compounds for ABCA1 upregulators. Compound E3317 (N-(6-butylbenzo[d]thiazol-2(3H)-ylidene)-3-(N-(2-cyanoethyl)sulfamoyl)benzamide)) was identified as a positive hit with an EC50value of 0.2 μM in ABCA1p-LUC HepG2 cells. Thus, we hypothesized that E3317 might have cholesterol- and lipid metabolism-regulating effects through ABCA1 upregulation. E3317 significantly increased ABCA1 mRNA and protein expression in hepatic L02 cells and RAW264.7 macrophages. E3317 promoted cholesterol efflux to apolipoprotein A-I in RAW264.7 macrophages and significantly decreased lipid accumulation in oxidized low-density lipoprotein-induced murine RAW264.7 macrophages. Further studies using ABCA1 siRNA showed that the promotion of cholesterol efflux and decrease of lipid accumulation by E3317 depended on ABCA1 expression. Mechanistic studies indicated that E3317 regulated ABCA1 expression via activating nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays an important role in the regulation of glucose homeostasis and lipid metabolism. The structure of E3317 was docked in the ligand-binding domain of PPARγ (PBD code: 4EMA) to find the key binding amino acids. Site mutation assays confirmed that Y327 and F363 were the key PPARγ binding epitopes of E3317. Our results revealed that E3317 upregulates ABCA1 expression and thereby promotes cholesterol efflux. E3317 may regulate ABCA1 expression through PPARγ. Our findings provide a new compound, E3317, which may have beneficial cardiovascular effects.
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影响因子：
--
作者：
Gao, Jie;Xu, Yanni;Si, Shuyi
通讯作者：
Si, Shuyi
影响因子：
15.9
作者：
Singaraja, RR;Fievet, C;Hayden, MR
通讯作者：
Hayden, MR
DOI：
--
发表时间：
2007
期刊：
--
影响因子：
--
作者：
N. J. McKenna
通讯作者：
N. J. McKenna
影响因子：
30.8
作者：
Bodzioch, M;Orsó, E;Schmitz, G
通讯作者：
Schmitz, G
影响因子：
--
作者：
B. Krause;B. Auerbach
通讯作者：
B. Krause;B. Auerbach