Cholesterol in Macrophages

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Science  29 Aug 2003:
Vol. 301, Issue 5637, pp. 1161
DOI: 10.1126/science.301.5637.1161b

The accumulation of dying macrophages in atherosclerotic lesions has been linked to rupture of plaques and subsequent thrombosis and ischemia. Studying how high cholesterol levels contribute to cell death, Feng et al. report that in mouse macrophages the toxicity of free cholesterol can be attributed to its transport to the endoplasmic reticulum (ER). Enrichment of this organelle in cholesterol triggered the unfolded protein response (UPR) stress pathway, which activated a transcription factor called CHOP (C/EBP homologous protein) and promoted programmed cell death. Macrophages derived from mice deficient in CHOP or in NPC1 (Niemann-Pick C), an endosomal protein required for intracellular trafficking of cholesterol, were resistant to free cholesterol-induced activation of UPR and cell death. Also, in the Apoe−/− mouse model of atherosclerosis, elevated plasma cholesterol increased CHOP expression in aortic lesions.

Feng et al. also report that macrophage apoptosis and lesional necrosis decreased in atherosclerotic lesions of Apoe−/− mice that were deficient in NPC1. Unlike the plasma membrane, the ER membrane is relatively fluid, and the authors propose that cholesterol loading of the ER membrane leads to depletion of lumenal calcium, perturbing membrane proteins involved in calcium homeostasis and triggering the UPR signaling pathway. — LDC

Nature Cell Biol. 10.1038/ncb1035 (2003); Proc. Natl. Acad. Sci. U.S.A. 100, 10423 (2003).

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