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.

The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis

“…How reduced sterol synthesis would counteract the toxic effects of ER stress remains unclear. One possible explanation would be that ER stress limits sterol exit through vesicular transport and a compensatory reduction in sterol synthesis becomes important to sustain basic ER functions, perhaps by maintaining appropriate membrane fluidity (Nilsson et al, 2001; Feng et al, 2003). In this way, RIDD (akin to other degradative pathways) could adjust basic metabolic parameters in the cell (Bernasconi et al, 2012).…”

7‐Ketocholesterol favors lipid accumulation and colocalizes with Nile Red positive cytoplasmic structures formed during 7‐ketocholesterol–induced apoptosis: Analysis by flow cytometry, FRET biphoton spectral imaging microscopy, and subcellular fractionation

“…These fast modifications in lipid content, especially in free cholesterol, can modify the structure and functions of some lipid-rich cellular compartments (endoplasmic reticulum, cytoplasmic membrane) and favor the relocation of molecules involved in the initiation of 7KC-induced cell death toward lipid rafts (cytoplasmic membrane microdomains rich in cholesterol and sphingolipids) involved in the initiation and transmission of various transduction signals, including cell death signals (56). Further, because free cholesterol activates apoptosis through the endoplasmic reticulum pathway (57), the intracellular accumulation of free cholesterol triggered by 7KC can stimulate some components of the endoplasmic reticulum, which in turn can induce 7KC-induced apoptosis. This hypothesis is supported by the expression of the cell death effector CHOP and GRP78/ bip chaperone, which are hallmarks of the unfolded protein response (58), and by the synthesis of similar cytoplasmic structures occurring under treatment with 7KC and free cholesterol (22,23,57,59).…”

Lipid signalling in disease

“…The accumulation of excess lipid, in particular saturated fatty acids and sterols, might induce cellular damage through stress on the membranes of lipid-metabolizing organelles, especially the endoplasmic reticulum (ER) and possibly mitochondria [56][57][58] . Under these conditions, the ER activates a complex response system known as the unfolded protein response (UPR) to restore the functional integrity of the organelle 59 .…”