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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Biological Transport, Active / drug effects
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Biological Transport, Active / physiology
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CCAAT-Enhancer-Binding Proteins / deficiency
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CCAAT-Enhancer-Binding Proteins / genetics
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Cells, Cultured
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Cholesterol / metabolism
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Cholesterol / toxicity*
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Coronary Artery Disease / metabolism*
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Coronary Artery Disease / physiopathology
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum / ultrastructure
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Female
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Intracellular Membranes / drug effects
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Intracellular Membranes / metabolism
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Intracellular Membranes / ultrastructure
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Macrophages / drug effects
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Macrophages / metabolism*
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Macrophages / pathology
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Mice
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Mice, Knockout
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Protein Folding*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transcription Factor CHOP
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Transcription Factors / deficiency
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Transcription Factors / genetics
Substances
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CCAAT-Enhancer-Binding Proteins
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Ddit3 protein, mouse
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Transcription Factors
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Transcription Factor CHOP
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Cholesterol