Abstract
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.
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Acknowledgements
This work was supported by National Institutes of Health (NIH) grants HL54591, HL57560 and HL56984 to I.T, DK47119 and ES08681 to D.R. and HL61814 to E.A.F. We gratefully acknowledge R. Soccio and F. Wang for assistance with the CHOP Taqman and in-situ hybridization assays, respectively. We also thank Y. Zhang for technical assistance and R. Jungreis for help with the Perk−/− and Chop−/− mice.
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Feng, B., Yao, P., Li, Y. et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5, 781–792 (2003). https://doi.org/10.1038/ncb1035
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DOI: https://doi.org/10.1038/ncb1035
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