雷公藤红素通过激活LXRα/ABCA1通路和细胞自噬抑制巨噬细胞脂质蓄积  

Celastrol Inhibits Lipid Accumulation by Activating The LXRΑ/ABCA1 Pathway and Lipophagyin Macrophages

作　　者：汪瑜翔 姜爽 石雅宁 张婵娟 刘乐平[4] 赵谭军 龚勇珍[1,2] 廖端芳[1,2] 覃丽[1,2] WANG Yu-Xiang;JIANG Shuang;SHI Ya-Ning;ZHANG Chan-Juan;LIU Le-Ping;ZHAO Tan-Jun;GONG Yong-Zhen;LIAO Duan-Fang;QIN Li(School of Pharmacy,Hunan University of Chinese Medicine,Changsha 410208,China;Ditision of Stem Cell Regulation and Application,Hunan Unitersity of Chinese Medicine,Changsha 410208,China;Department of Pharmacy,Hunan Traditional Chinese Medical College,Zhuzhou 412012,China;Institue of lunovation and Applied Research in Chinese Medicine,HunanUniversity of Chinese Medicine,Changsha 410208,China)

机构地区：[1]湖南中医药大学药学院,长沙410208 [2]湖南中医药大学干细胞中药调控与应用实验室,长沙410208 [3]湖南中医药高等专科学校药学系,株洲412012 [4]湖南中医药大学科技创新中心,长沙410208

出　　处：《生物化学与生物物理进展》2021年第7期836-845,共10页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(81973668,81774130,81670268);湖南省自然科学基金杰出青年基金(2018JJ1018);长沙市科技计划(kq2004060);湖南省研究生教育创新工程和专业能力提升工程(CX20200755);湖南省药学一流学科资助项目。

摘　　要：巨噬细胞源性泡沫细胞转化被认为是动脉粥样硬化(atherosclerosis,AS)形成与发展的早期变化,其细胞内蓄积的过量脂质可通过促进血管内膜生长与坏死核形成,继而诱发斑块破裂及血栓形成等严重后果.近期研究发现,雷公藤红素可显著调节脂质代谢,对泡沫细胞转化进程具有潜在的治疗意义.本研究表明,雷公藤红素(Celasrol,CeT)呈浓度依赖性减少巨噬细胞Raw264.7内的脂滴积蓄,并上调胆固醇转运关键分子ABCA1、LXRA蛋白质表达.进一步研究显示,CeT可逆转ABCA1敲低介导的脂质蓄积与ABCA1表达下调.此外,CeT处理Raw264.7细胞24 h时观察到自噬标志物LC3Ⅱ/Ⅰ增加、p62减少,且采用自噬抑制剂3MA可恢复细胞内脂质水平.综上,CeT可能通过上调LXRα/ABCA1信号及激活荷脂细胞自噬,抑制巨噬细胞内脂质蓄积.因此,深入探究CeT在巨噬细胞源性泡沫细胞转化及AS发生发展中的作用,是研究AS治疗新的着力点,并为药物干预提供新的靶点.Macrophage-derived foam cell transformation is considered to be an early change in the formation and development of atherosclerosis(AS). Excessive lipid accumulation in the macrophage-derived foam cell often promotes vascular intimal growth and necrosis, which leads to plaque instability and thrombosis. Recent evidence indicated that Celasrol(CeT) can significantly regulate lipid metabolism, which has potential therapeutic significance in the process of foam cell transformation. In this study, CeT treatment can reduce the accumulation of lipid droplets in lipid-loaded Raw264.7 cell in concentration-dependent manner, and up-regulate the protein expression of ABCA1 and LXRα, the key molecules of cholesterol transport in Raw264.7. In addition, the results showed that knockdown of ABCA1 promoted lipid storage, while CeT reduced intracellular lipid accumulation and up-regulated ABCA1 expression. Moreover, LC3 Ⅱ/Ⅰ ratio was increased and p62 was decreased after treatment with CeT for 24 h. Besides, the intracellular lipid level was restored following exposure to autophagy inhibitor 3 MA. In summary, CeT can reduce intracellular lipid accumulation by up-regulating LXRα/ABCA1 signal and activating autophagy of lipocytes. Therefore, further study about the role of CeT in the transformation of macrophage derived foam cells may be a promising strategy for AS therapy and underlying target for drug intervention.

关 键 词：雷公藤红素 动脉粥样硬化 LXRα/ABCA1信号通路 自噬 

分 类 号：R966[医药卫生—药理学]