成纤维细胞生长因子21通过诱导自噬促进泡沫细胞胆固醇流出  

Fibroblast growth factor 21 promotes cholesterol efflux from foam cells by inducing autophagy

作　　者：赵金理 孟军[2] 曾召林 夏林珍 陈姣姣 王佐[1] ZHAO Jinli-;MENG Jun;ZENG Zhaolin;XIA Linzhen;CHEN Jiaojiao;WANG Zuo(Institute of Cardiovascular Disease Research&Key Laboratory for AtheroscLeroLogy of Hunan Province,University of South China,Hengyang,Hunan 421001,China;The First Affiliated Hospital,Uinversity of South China,Hengyang,Hunan 421001,China;People's Hospital of Nanchuan District,Chongqing 510370,China)

机构地区：[1]南华大学心血管病研究所动脉硬化学湖南省重点实验室,湖南省衡阳市421001 [2]南华大学附属第一医院,湖南省衡阳市421001 [3]重庆市南川区人民医院,重庆市510370

出　　处：《中国动脉硬化杂志》2020年第6期468-474,共7页Chinese Journal of Arteriosclerosis

基　　金：国家自然科学基金项目(81600342,81970389);湖南省研究生科研创新项目(CX20190752)。

摘　　要：目的探讨成纤维细胞生长因子21(FGF21)促进泡沫细胞胆固醇流出的机制。方法在建立THP-1巨噬细胞源性泡沫细胞模型的基础上,以不同浓度(0、50、100、200、400μg/L)FGF21处理泡沫细胞24 h,以200μg/L FGF21处理泡沫细胞不同时间(0、6、12、24、48 h),Western blot、激光共聚焦检测LC3,MDC染色分析自噬小体,HPLC、油红O染色测定细胞内胆固醇蓄积,液体闪烁计数分析胆固醇流出。结果 200、400μg/L的FGF21,以及200μg/L的FGF21作用24 h和48 h,泡沫细胞总胆固醇(TC)、游离胆固醇(FC)和胆固醇酯(CE)水平均显著降低,而其胆固醇流出显著增强。机制研究发现,FGF21可诱导泡沫细胞自噬体形成,且微管相关蛋白Ⅰ轻链3(LC3-Ⅰ)至微管相关蛋白Ⅱ轻链3(LC3-Ⅱ)转化率显著增加,但自噬相关基因5(ATG5)siRNA或3-甲基腺嘌呤(3-MA)或巴弗洛霉素A1(BafA1)干预自噬后,FGF21对TC、FC和CE的降低作用减弱,同时胆固醇流出减少,泡沫细胞脂质蓄积加重。结论 FGF21通过上调自噬促进泡沫细胞胆固醇流出。Aim To investigate the mechanism of fibroblast growth factor 21(FGF21) in promoting cholesterol efflux from foam cells. Methods THP-1 derived foam cells were treated with FGF21 at different concentrations(0, 50, 100, 200, 400 μg/L) for 24 hours and 200 μg/L FGF21 at different time(0, 6, 12, 24, 48 h), Western blot, laser confocal were used to detect LC3, and MDC staining for autophagosomes analysis, HPLC, oil red O staining for intracellular cholesterol accumulation measurement, and liquid scintillation counting for cholesterol efflux detection. Results After 200 μg/L, 400 μg/L FGF21 and 200 μg/L FGF21 were applied for 24 h and 48 h, the levels of total cholesterol(TC), free cholesterol(FC) and cholesterol ester(CE) in foam cells were significantly reduced, while their cholesterol efflux was significantly enhanced. Mechanism studies found that FGF21 induced the formation of autophagosomes in foam cells, and the conversion rate of microtubule-associated protein Ⅰ light chain3(LC3-Ⅰ) to microtubule-associated protein Ⅱ light chain3(LC3-Ⅱ) was significantly increased. However, after autophagy was inhibited with autophagy-related gene 5(ATG5) siRNA or 3-methyladenine(3-MA) or Bafilomyein A1(BafA1), effect of FGF21 on decreasing TC, FC, CE and lipid accumulation, and increasing cholesterol efflux were reduced. Conclusion FGF21 promotes cholesterol efflux in foam cells by up-regulating autophagy.

关 键 词：成纤维细胞生长因子21 泡沫细胞 自噬 脂质蓄积 胆固醇流出 

分 类 号：R363[医药卫生—病理学] R5[医药卫生—基础医学]