依泽替米贝通过SIRT1抑制血管平滑肌细胞源性荷脂细胞固醇调节元件结合蛋白1c的过度乙酰化  

Ezetimibe Inhibit Hyperacetylation of SREBP-1c in Lipid-Loaded Cells Derived from VSMC Required for SIRT1

作　　者：张弛[1] 黄靓[1] 罗其富[2] 屈顺林[1] 韦星[1] 唐志晗[1] 高治平[2] 

机构地区：[1]南华大学心血管疾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]南华大学药物药理研究所,湖南省衡阳市421001

出　　处：《中国动脉硬化杂志》2012年第6期519-522,共4页Chinese Journal of Arteriosclerosis

基　　金：湖南省教育厅基金项目(08C743)

摘　　要：目的探讨依泽替米贝对血管平滑肌细胞源性荷脂细胞固醇调节元件结合蛋白1c乙酰化水平的影响及其分子机制。方法采用20 mg/L胆固醇∶β-环糊精混合物处理原代培养的大鼠主动脉平滑肌细胞制备荷脂细胞模型,经30μmol/L依泽替米贝处理荷脂细胞24 h后,通过Western blot检测固醇调节元件结合蛋白1c的乙酰化修饰水平及脂肪酸合成酶表达的改变,免疫共沉淀技术检测固醇调节元件结合蛋白1c与SIRT1的相互作用,转染shRNA抑制SIRT1的表达研究SIRT1在依泽替米贝调节固醇调节元件结合蛋白1c乙酰化水平中的作用。结果血管平滑肌细胞经20 mg/L胆固醇∶β-环糊精混合物处理48 h后,固醇调节元件结合蛋白1c的乙酰化修饰水平升高,脂肪酸合成酶的表达增加,固醇调节元件结合蛋白1c与SIRT1蛋白的相互作用降低,但依泽替米贝处理后能够改善胆固醇∶β-环糊精混合物所引起的血管平滑肌细胞的这一系列改变。然而,若利用SIRT1 shRNA抑制细胞SIRT1的表达则能够废除依泽替米调节固醇调节元件结合蛋白1c过度乙酰化的作用。结论依泽替米贝通过SIRT1抑制血管平滑肌源性荷脂细胞固醇调节元件结合蛋白1c的过度乙酰化。AimThe effect of ezetimibe（EZE） on acetylation of sterol regulatory element binding protein-1c（SREBP-1c） in lipid-loaded cells derived from vascular smooth muscle cell（VSMC） and its mechanisms have been explored.Methods The cholesterol∶methyl-β-cyclodextrin（Chol∶MβCD） complexes were used to build VSMC-derived lipid-loaded cells.After treated by 30 μmol/L EZE,the level of acetylated SREBP-1c,the level of fatty acid synthase（FAS） protein expression in lipid-loaded cells were detected by western blot,and the interaction between SIRT1 and SREBP-1c were analyzed by co-immunoprecipitation,and the role of SIRT1 in deacetylation of SREBP-1c was investigated using shRNA-mediated protein knockdown.Results The level of acetylated SREBP-1c,the level of FAS protein expression were increased,but the interaction between SIRT1 and SREBP-1c was significantly reduced in lipid-loaded cells.However,EZE could weaken all these effects induced by Chol∶MβCD in lipid-loaded cells.A further study reveals that effects of EZE in lipid-loaded cells could be abolished by SIRT1 shRNA transfection.ConclusionEZE inhibits hyperacetylation of SREBP-1c in lipid-loaded cells required for SIRT1.

关 键 词：依泽替米贝 血管平滑肌细胞 固醇调节元件结合蛋白1C SIRT1 乙酰化修饰 

分 类 号：R363[医药卫生—病理学]