Minimally modified low-density lipoprotein induces macrophage endoplasmic reticulum stress via toll-like receptor 4.
Minimally modified low-density lipoprotein induces macrophage endoplasmic reticulum stress via toll-like receptor 4.
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DOI：
10.1016/j.bbalip.2012.03.003
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发表时间：
2012-07
期刊：
影响因子：
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通讯作者：
Shutong Yao;Nana Yang;Guohua Song;H. Sang;Hua Tian;C. Miao;Ying Zhang;S. Qin
中科院分区：
文献类型：
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作者：
Shutong Yao;Nana Yang;Guohua Song;H. Sang;Hua Tian;C. Miao;Ying Zhang;S. Qin
最小修饰的低密度脂蛋白（mm-LDL）诱导内膜泡沫细胞形成，这是由内质网应激（ERS）促进的，内质网应激是一个交叉点，将细胞过程与动脉粥样硬化所有阶段中存在的多种危险因素联系起来。然而，目前还不清楚是否mm-LDL诱导的巨噬细胞中的脂质积聚涉及ERS及其潜在的机制。我们发现，毫米低密度脂蛋白诱导的脂肪滴在RAW 264.7巨噬细胞的积累，增加游离胆固醇的内质网，这是显着减弱预处理与Toll样受体4（TLR 4）的抗体。此外，mm-LDL刺激Cy 3标记的激活转录因子6（ATF 6），未折叠蛋白反应（UPR）的关键传感器，从细胞质到细胞核的运输。磷酸化肌醇需要酶1（p-IRE 1），另一个传感器的UPR，和它的两个下游分子，X盒结合蛋白1和葡萄糖调节蛋白78（GRP 78）的表达，显着上调mm-LDL。抗TLR 4或CD 36抗体均能显著抑制mm-LDL诱导的上述改变。TLR 4 siRNA可显著抑制mm-LDL诱导的p-IRE 1和GRP 78的表达上调以及ATF 6的核转位。这些结果表明，mm-LDL可以诱导游离胆固醇在内质网中的积累，随后刺激ERS和激活巨噬细胞中由ATF 6和IRE 1介导的UPR信号通路，这一过程可能由TLR 4介导。
Minimally modified low-density lipoprotein (mm-LDL) induces intimal foam cell formation, which is promoted by endoplasmic reticulum stress (ERS), a cross-point to link cellular processes with multiple risk factors that exist in all stages of atherosclerosis. However, it remains unclear whether mm-LDL-induced lipid accumulation in macrophages involves ERS and its underlying mechanisms. We showed that mm-LDL induced the accumulation of lipid droplets in RAW264.7 macrophages with increased free cholesterol in the endoplasmic reticulum, which was markedly attenuated by pretreatment with an antibody against toll-like receptor 4 (TLR4). Additionally, mm-LDL stimulated the transport of Cy3-labeled activating transcription factor 6 (ATF6), a key sensor to the unfolded protein response (UPR), from cytoplasm into nucleus. The expression of phosphorylated inositol-requiring enzyme 1 (p-IRE1), another sensor to the UPR, and its two downstream molecules, X box binding protein 1 and glucose-regulated protein 78 (GRP78), were significantly upregulated by mm-LDL. The alterations induced by mm-LDL were all significantly inhibited by antibodies against TLR4 or CD36. In addition, the upregulation of p-IRE1 and GRP78 and the nuclear translocation of ATF6 induced by mm-LDL were significantly attenuated by TLR4 siRNA. These results suggest that mm-LDL may induce free cholesterol accumulation in the endoplasmic reticulum and subsequently stimulate ERS and activate the UPR signaling pathway mediated by ATF6 and IRE1 in macrophages, a process that is potentially mediated by TLR4.