野黄芩素通过促进胆固醇外流途径抑制巨噬细胞泡沫化的作用机制  

Mechanism of scutellarein inhibiting foaming of macrophages by promoting cholesterol efflux pathway

作　　者：吴若琳 黄裕鸿 王天琦 孙文龙 李敬达 WU Ruo-lin;HUANG Yu-hong;WANG Tian-qi;SUN Wen-long;LI Jing-da(College of Life Science,Yangtze University,Jingzhou Hubei 434000,China;College of Agriculture,Yangtze University,Jingzhou Hubei 434000,China;School of Life Sciences and Medicine,Shandong University of Technology,Zibo Shandong 255000,China)

机构地区：[1]长江大学生命科学学院,湖北荆州434000 [2]长江大学农学院,湖北荆州434000 [3]山东理工大学生命与医药学院,山东淄博255000

出　　处：《中国药理学通报》2023年第12期2266-2273,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学青年科学基金资助项目(No 82004020);国家自然科学青年科学基金资助项目(No 81903878)。

摘　　要：目的探究野黄芩素对巨噬细胞泡沫化及胆固醇外流作用的影响及潜在机制。方法使用佛波醇12-十四酸酯13-乙酸酯(PMA)诱导THP-1细胞巨噬化,并通过MTT法检测不同浓度野黄芩素对巨噬细胞活力的影响;利用胆固醇含量检测试剂盒及NBD荧光标记胆固醇测定不同浓度野黄芩素对巨噬细胞胆固醇蓄积和外流作用的干预效果;采用分子对接、ELISA、双荧光素酶报告基因和Western blot法确定野黄芩素对PPARγ-LXRα-ABCA1信号通路的激活情况;利用siRNA干扰技术分析PPARγ基因沉默对野黄芩素增强胆固醇外流途径和抑制巨噬细胞泡沫化的影响。结果野黄芩素可剂量依赖性地抑制oxLDL诱导的胆固醇蓄积,加速胆固醇外流途径并明显提高LXRα和ABCA1蛋白表达;同时,野黄芩素可结合PPARγ,并启动其下游LXRα-ABCA1信号通路。此外,PPARγ的基因沉默不仅明显抑制了野黄芩素诱导的LXRα-ABCA1信号通路和胆固醇外流途径,还可逆转野黄芩素对巨噬细胞泡沫化的抑制作用。结论野黄芩素可激活PPARγ并通过启动下游LXR-ABCA1信号通路,促进胆固醇外流途径,进而抑制巨噬细胞泡沫化。Aim To investigate the effects of scutellarein on the macrophage foam cell formation and cholesterol efflux,and the underlying mechanism.Methods THP-1 cells were differentiated with PMA,and the cell viability was detected by MTT assays.The effects of scutellarein on the cholesterol efflux and macrophage foam cell formation were evaluated by using NBD-labeled cholesterol and the cholesterol detection kit.The effects of scutellarein on the activation of PPARγ-LXRα-ABCA1 signaling pathway were determined by molecular docking,ELISA,dual-luciferase reporter and Western blot.The effects of PPARγknowdown on scutellarein-induced cholesterol efflux and inhibiting macrophage foaming were analyzed by siRNA interference.Results Scutellarein dose-dependently inhibited oxLDL-induced cholesterol accumulation,accelerated cholesterol efflux and significantly increased the protein expression of LXRαand ABCA1.At the same time,scutellarein could bind PPARγand initiate its downstream LXRα-ABCA1 signaling pathway.In addition,gene silencing of PPARγnot only significantly inhibited scutellarein-induced LXRα-ABCA1 signaling pathway and cholesterol efflux,but also reversed the inhibitory effect of scutellarein on macrophage foaming.Conclusions Scutellarein could promote the cholesterol efflux by activating PPARγand initiating the downstream LXR-ABCA1 signaling pathway,thereby prevent the macrophage foam cell formation.

关 键 词：野黄芩素 动脉粥样硬化 氧化低密度脂蛋白 PPARγ 巨噬细胞泡沫化 胆固醇外流 

分 类 号：R284.1[医药卫生—中药学] R329.24[医药卫生—中医学] R341.35R344.8R543.5