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

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.

Yao S ，Yang N ，Song G ，Sang H ，Tian H ，Miao C ，Zhang Y ，Qin S ... -  《-》

[Oxidized low density lipoprotein induces macrophage endoplasmic reticulum stress via CD36.].

Yao ST ，Sang H ，Yang NN ，Kang L ，Tian H ，Zhang Y ，Song GH ，Qin SC ... -  《-》

Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression.

Yao S ，Miao C ，Tian H ，Sang H ，Yang N ，Jiao P ，Han J ，Zong C ，Qin S ... -  《-》

Activating transcription factor 6 mediates oxidized LDL-induced cholesterol accumulation and apoptosis in macrophages by up-regulating CHOP expression.

Yao S ，Zong C ，Zhang Y ，Sang H ，Yang M ，Jiao P ，Fang Y ，Yang N ，Song G ，Qin S ... -  《-》

Quercetin protects macrophages from oxidized low-density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress-C/EBP homologous protein pathway.

Yao S ，Sang H ，Song G ，Yang N ，Liu Q ，Zhang Y ，Jiao P ，Zong C ，Qin S ... -  《-》