锌指Krüppel样因子4抑制平滑肌内源性脂合成的新功能及其分子机制研究

项目名称： 锌指Krüppel样因子4抑制平滑肌内源性脂合成的新功能及其分子机制研究

项目编号： No.31271493

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 秦晓梅

作者单位： 北京大学

项目金额： 80万元

中文摘要： 平滑肌内源性(endogenous)脂质合成异常是动脉粥样硬化(AS)早期首要病理环节。锌指Krüppel样因子4(KLF4)是我们前期研究中新近发现的一种调节血管脂代谢的关键因子，前期和预实验结果表明：KLF4介导了脉冲式层流诱导的内皮insig1表达；KLF4可显著降低IL-1诱导的平滑肌内源性脂质积聚。然而,KLF4是否直接调控平滑肌内源性脂质合成及其机制尚不明确。 本研究以KLF4抑制平滑肌内源性脂质合成(de novo lipogenesis)的新功能及机制为靶点，将分子细胞生物学、生物信息学与动物模型相交叉、整合，首次1）阐明KLF4对内源性脂合成的影响及调控机制；2）探讨KLF4对炎症诱导的平滑肌脂质合成异常增加的影响；3）揭示KLF4新功能的表型转归。循分子-细胞-整体水平阐释KLF4抗平滑肌内源性脂质合成的分子病理生理学机制及其意义,藉此为AS机理研究开辟新途经。

中文关键词： 平滑肌细胞；脂代谢；动脉粥样硬化；；

英文摘要： Enhanced and disordered in situ lipogenesis in vascular smooth muscle cells(VSMCs) maybe the earliest and the primary event in the development of atheroma. Krüppel-like factor 4(KLF4) is a zinc-finger transcription factor that plays a critical role in the regulation of cellular proliferation, differentiation and oncogenesis. KLF4 has been newly identified as a key regulator controlling lipid metabolism in blood vessels in our study.Indeed,a strong association between KLF4 expression and de novo lipogenesis has been implied in our experiments, conferring an advantage to VSMCs. Our previous studies have demonstrated that silencing of KLF4 by small interfering RNA in endothelial cells permits a decrease in pulsatile laminar shear stress-stimulated insig1 expression. Furthermore, our preliminary data have also revealed that KLF4 substantially inhibited the interleukin-1(IL-1)-induced lipogenic enzymes expression and intracellular accumulation of neutral lipids, which are storage products of fatty acid and cholesterol in VSMCs.Although remarkable progress has been achieved, much less is known concerning whether KLF4 directly modulates the de novo lipogenesis in VSMCs,and the molecular mechanisms by which this occurs have not yet been defined. Therefore, it is essential to elucidate the novel role that KLF4 exerts in

英文关键词： smooth muscle cells；lipid metablism；atherosclerosis；；