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The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages

Nature Cell Biology volume 5, pages 781–792 (2003)Cite this article

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.

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Figure 1: Free-cholesterol-induced apoptosis in macrophages is blocked by a low dose of U18666A.
Figure 2: The endoplasmic reticulum, not the plasma membrane, is the site of cholesterol-Induced apoptosis.
Figure 3: Free cholesterol loading of macrophages activates the UPR.
Figure 4: CHOP is expressed in the atherosclerotic lesions of Apoe−/− mice.
Figure 5: Free cholesterol loading depletes endoplasmic reticulum calcium stores.
Figure 6: Disruption of the PERK enhances cholesterol-induced apoptosis.
Figure 7: Disruption of CHOP attenuates free-cholesterol-induced apoptosis in macrophages.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants HL54591, HL57560 and HL56984 to I.T, DK47119 and ES08681 to D.R. and HL61814 to E.A.F. We gratefully acknowledge R. Soccio and F. Wang for assistance with the CHOP Taqman and in-situ hybridization assays, respectively. We also thank Y. Zhang for technical assistance and R. Jungreis for help with the Perk−/− and Chop−/− mice.

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Authors and Affiliations

  1. Departments of Medicine and Cell Biology, Columbia University, New York, 10032, NY, USA

    Bo Feng, Pin Mei Yao, Yankun Li, Cecilia M. Devlin, Dajun Zhang, George Kuriakose & Ira Tabas

  2. Skirball Institute, New York University School of Medicine, New York, 10016, NY, USA

    Heather P. Harding & David Ron

  3. Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Columbia University, New York, 10032, NY, USA

    Michele Sweeney & Andrew R. Marks

  4. Department of Medicine and The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, 10029, NY, USA

    James X. Rong & Edward A. Fisher

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Feng, B., Yao, P., Li, Y. et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5, 781–792 (2003). https://doi.org/10.1038/ncb1035

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