IRAK1 mediates TLR4-induced ABCA1 downregulation and lipid accumulation in VSMCs.
IRAK1 mediates TLR4-induced ABCA1 downregulation and lipid accumulation in VSMCs.
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IRAK1 介导 TLR4 诱导的 ABCA1 下调和 VSMC 中脂质积累
DOI：
10.1038/cddis.2015.212
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发表时间：
2015-10-29
影响因子：
9
通讯作者：
Li JC
中科院分区：
文献类型：
--
作者：
Guo L;Chen CH;Zhang LL;Cao XJ;Ma QL;Deng P;Zhu G;Gao CY;Li BH;Pi Y;Liu Y;Hu ZC;Zhang L;Yu ZP;Zhou Z;Li JC
Toll样受体4(TLR4)信号的激活在促进血管平滑肌细胞(VSMCs)的脂质堆积和促炎作用中起着重要作用，从而促进动脉粥样硬化的发生和发展。以往的研究表明，VSMC中脂质的过度积累是由于抑制了ATP结合盒转运体A1(ABCA1)的表达，ABCA1是VSMC中脂质外流的重要分子介质。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信号调控ABCA1表达的分子机制。用50μg/ml氧化型低密度脂蛋白(OxLDL)刺激原代培养的VSMC。我们确定，使用oxLDL增强TLR4信号显著下调ABCA1的表达，并诱导VSMC中的脂质积累。然而，TLR4基因敲除显著地挽救了oxLDL诱导的ABCA1下调和脂质堆积。此外，IL-1R相关激酶1(IRAK1)参与了TLR4信号对ABCA1表达和脂质堆积的影响。使用特定的siRNA沉默IRAK1的表达，在体外逆转了TLR4诱导的ABCA1下调和脂质积累。我们的活体实验进一步证实了这些结果。我们确定，通过给予小鼠长达12周的高脂饮食(HFD)来增强TLR4信号显著增加IRAK1的表达，从而下调ABCA1的表达并诱导脂质积累。此外，体内TLR4基因敲除逆转了HFD对IRAK1和ABCA1表达以及对脂质积累的影响。综上所述，IRAK1参与了TLR4介导的ABCA1表达下调和VSMCs的脂质积累。
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.