The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages - PubMed (original) (raw)
doi: 10.1038/ncb1035. Epub 2003 Aug 10.
Pin Mei Yao, Yankun Li, Cecilia M Devlin, Dajun Zhang, Heather P Harding, Michele Sweeney, James X Rong, George Kuriakose, Edward A Fisher, Andrew R Marks, David Ron, Ira Tabas
Affiliations
- PMID: 12907943
- DOI: 10.1038/ncb1035
The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages
Bo Feng et al. Nat Cell Biol. 2003 Sep.
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.
Comment in
- Unfolding the toxicity of cholesterol.
Zhang K, Kaufman RJ. Zhang K, et al. Nat Cell Biol. 2003 Sep;5(9):769-70. doi: 10.1038/ncb0903-769. Nat Cell Biol. 2003. PMID: 12951604 No abstract available.
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