Minimally modified low-density lipoprotein induces macrophage endoplasmic reticulum stress via toll-like receptor 4

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• 作者：Shutong Yao^a ; ^b ; ^{yst228@126.com} ; Nana Yang^a ; ^{benben1980@126.com} ; Guohua Song^a ; ^b ; ^{girl_sapphire@hotmail.com} ; Hui Sang^a ; ^b ; ^{sanghuiy@163.com} ; Hua Tian^a ; ^{xueyu2006823@yahoo.com.cn} ; Cheng Miao^a ; ^{miaoch_1987@163.com} ; Ying Zhang^a ; ^{sdyrx@163.com} ; Shucun Qin^a ; ^b ; ^{shucunqin@hotmail.com}
• 关键词：AS ; atherosclerosis ; LDL ; low-density lipoprotein ; mm-LDL ; minimally modified LDL ; ERS ; endoplasmic reticulum stress ; ox-LDL ; oxidative modified LDL ; GRP78 ; glucose-regulated proteins 78 ; IRE1 ; inositol-requiring enzyme 1 ; ATF6 ; activating transcription f
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：July, 2012
• 卷：1821
• 期：7
• 页码：954-963
• 文件大小：1991 K

摘要

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.