The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages.
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.
Feng
Bo
B
Department of Medicine, Columbia University, New York, NY 10032, USA.
Yao
Pin Mei
PM
Li
Yankun
Y
Devlin
Cecilia M
CM
Zhang
Dajun
D
Harding
Heather P
HP
Sweeney
Michele
M
Rong
James X
JX
Kuriakose
George
G
Fisher
Edward A
EA
Marks
Andrew R
AR
Ron
David
D
Tabas
Ira
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000172:deficiency / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism / Q000633:toxicity*; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017510:Protein Folding; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D002784:Cholesterol