title: The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages.
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.
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Pin Mei
authors.initials: PM
authors.lastname: Yao
authors.forename: Yankun
authors.initials: Y
authors.lastname: Li
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Devlin
authors.forename: Dajun
authors.initials: D
authors.lastname: Zhang
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: Michele
authors.initials: M
authors.lastname: Sweeney
authors.forename: James X
authors.initials: JX
authors.lastname: Rong
authors.forename: George
authors.initials: G
authors.lastname: Kuriakose
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: 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
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D002784:Cholesterol