The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages
The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages
复制标题
DOI：
10.1038/ncb1035
复制
发表时间：
2003-09-01
影响因子：
21.3
通讯作者：
Tabas, I
中科院分区：
文献类型：
--
作者：
Feng, B;Yao, PM;Tabas, I
过量的细胞胆固醇会诱导巨噬细胞凋亡，这一事件可能促进动脉粥样硬化的进展。胆固醇诱导细胞凋亡的细胞机制尚不清楚，但以前被认为涉及质膜。在这里，我们报道内质网中的未折叠蛋白反应（UPR）在负载胆固醇的巨噬细胞中被激活，导致细胞死亡效应器 CHOP 的表达。胆固醇负荷会耗尽内质网钙储存，这是已知会诱导 UPR 的事件。此外，通过选择性抑制胆固醇向内质网的运输，内质网钙消耗、UPR、caspase-3激活和细胞凋亡受到显着抑制，并且Chop(-/-)巨噬细胞免受胆固醇诱导的细胞凋亡。我们认为，胆固醇转运至内质网膜，导致 UPR 的 CHOP 臂激活，是胆固醇诱导巨噬细胞凋亡的关键信号传导步骤。
Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterol-loaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop(-/-) macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.