| First Author | McAlpine CS | Year | 2014 |
| Journal | J Lipid Res | Volume | 55 |
| Issue | 11 | Pages | 2320-33 |
| PubMed ID | 25183803 | Mgi Jnum | J:216137 |
| Mgi Id | MGI:5607793 | Doi | 10.1194/jlr.M051094 |
| Citation | McAlpine CS, et al. (2014) Protein kinase R-like endoplasmic reticulum kinase and glycogen synthase kinase-3alpha/beta regulate foam cell formation. J Lipid Res 55(11):2320-33 |
| abstractText | Evidence suggests a causative role for endoplasmic reticulum (ER) stress in the development of atherosclerosis. This study investigated the potential role of glycogen synthase kinase (GSK)-3alpha/beta in proatherogenic ER stress signaling. Thp1-derived macrophages were treated with the ER stress-inducing agents, glucosamine, thapsigargin, or palmitate. Using small-molecule inhibitors of specific unfolded protein response (UPR) signaling pathways, we found that protein kinase R-like ER kinase (PERK), but not inositol requiring enzyme 1 or activating transcription factor 6, is required for the activation of GSK3alpha/beta by ER stress. GSK3alpha/beta inhibition or siRNA-directed knockdown attenuated ER stress-induced expression of distal components of the PERK pathway. Macrophage foam cells within atherosclerotic plaques and isolated macrophages from ApoE(-/-) mice fed a diet supplemented with the GSK3alpha/beta inhibitor valproate had reduced levels of C/EBP homologous protein (CHOP). GSK3alpha/beta inhibition blocked ER stress-induced lipid accumulation and the upregulation of genes associated with lipid metabolism. In primary mouse macrophages, PERK inhibition blocked ER stress-induced lipid accumulation, whereas constitutively active S9A-GSK3beta promoted foam cell formation and CHOP expression, even in cells treated with a PERK inhibitor. These findings suggest that ER stress-PERK-GSK3alpha/beta signaling promotes proatherogenic macrophage lipid accumulation. |
