Guo L, Chen C-H, Zhang L-L, Cao X-J, Ma Q-L, Deng P, Zhu G, Gao C-Y, Li B-H, Pi Y, Liu Y, Hu Z-C, Zhang L, Yu Z-P, Zhou Z, Li J-C
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
Cell Death Dis. 2015 Oct 29;6(10):e1949. doi: 10.1038/cddis.2015.212.
The activation of Toll-like receptor 4 (TLR4) signaling has an important role in promoting lipid accumulation and pro-inflammatory effects in vascular smooth muscle cells (VSMCs), which facilitate atherosclerosis development and progression. Previous studies have demonstrated that excess lipid accumulation in VSMCs is due to an inhibition of the expression of ATP-binding cassette transporter A1 (ABCA1), an important molecular mediator of lipid efflux from VSMCs. However, the underlying molecular mechanisms of this process are unclear. The purpose of this study was to disclose the underlying molecular mechanisms of TLR4 signaling in regulating ABCA1 expression. Primary cultured VSMCs were stimulated with 50 μg/ml oxidized low-density lipoprotein (oxLDL). We determined that enhancing TLR4 signaling using oxLDL significantly downregulated ABCA1 expression and induced lipid accumulation in VSMCs. However, TLR4 knockout significantly rescued oxLDL-induced ABCA1 downregulation and lipid accumulation. In addition, IL-1R-associated kinase 1 (IRAK1) was involved in the effects of TLR4 signaling on ABCA1 expression and lipid accumulation. Silencing IRAK1 expression using a specific siRNA reversed TLR4-induced ABCA1 downregulation and lipid accumulation in vitro. These results were further confirmed by our in vivo experiments. We determined that enhancing TLR4 signaling by administering a 12-week-long high-fat diet (HFD) to mice significantly increased IRAK1 expression, which downregulated ABCA1 expression and induced lipid accumulation. In addition, TLR4 knockout in vivo reversed the effects of the HFD on IRAK1 and ABCA1 expression, as well as on lipid accumulation. In conclusion, IRAK1 is involved in TLR4-mediated downregulation of ABCA1 expression and lipid accumulation in VSMCs.
Toll样受体4（TLR4）信号通路的激活在促进血管平滑肌细胞（VSMC）脂质蓄积和促炎作用方面发挥重要作用，而这有助于动脉粥样硬化的发生和发展。既往研究表明，VSMC中脂质过度蓄积是由于三磷酸腺苷结合盒转运体A1（ABCA1）表达受到抑制，ABCA1是VSMC脂质流出的重要分子介质。然而，这一过程的潜在分子机制尚不清楚。本研究旨在揭示TLR4信号通路调节ABCA1表达的潜在分子机制。用50μg/ml氧化低密度脂蛋白（oxLDL）刺激原代培养的VSMC。我们发现，使用oxLDL增强TLR4信号通路可显著下调VSMC中ABCA1的表达并诱导脂质蓄积。然而，TLR4基因敲除可显著挽救oxLDL诱导的ABCA1下调和脂质蓄积。此外，白细胞介素-1受体相关激酶1（IRAK1）参与了TLR4信号通路对ABCA1表达和脂质蓄积的影响。使用特异性小干扰RNA（siRNA）沉默IRAK1表达可在体外逆转TLR4诱导的ABCA1下调和脂质蓄积。我们的体内实验进一步证实了这些结果。我们发现，给小鼠喂食12周高脂饮食（HFD）以增强TLR4信号通路，可显著增加IRAK1表达，从而下调ABCA1表达并诱导脂质蓄积。此外，体内TLR4基因敲除可逆转HFD对IRAK1和ABCA1表达以及脂质蓄积的影响。总之，IRAK1参与了TLR4介导的VSMC中ABCA1表达下调和脂质蓄积过程。
