Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis

  • An Erratum to this article was published on 01 February 2010


Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid–binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.

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Figure 1: PBA treatment protects against macrophage ER stress and reduces vascular disease progression.
Figure 2: Requirement for aP2 in lipid-induced ER stress and apoptosis.
Figure 3: aP2 deficiency protects from hypercholesteremia-induced macrophage ER stress and apoptosis in atherosclerotic lesions.
Figure 4: Regulation of macrophage lipid composition by aP2.
Figure 5: A central role for SCD and C16:1n7 in aP2 mediated lipotoxic signaling.
Figure 6: Linking toxic lipids to ER stress and atherosclerosis through aP2–LXR-α crosstalk.

Change history

  • 04 February 2010

    In the version of this article initially published, the official symbol for the gene encoding the aP2 protein was misidentified as Tcfap2a (the gene symbol for the transcription factor AP-2). The correct gene symbol is Fabp4. In no instances anywhere in the study was AP-2 examined. Additionally, Supplementary Figure 2a should also have been cited where Figure 2c was cited. The errors have been corrected in the HTML and PDF versions of the article.


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This project has been supported by grants from the US National Institutes of Health DK DK52539 (to G.S.H.), HL65405 (to M.F.L. and G.S.H.) and DK59637 (Lipid, Lipoprotein and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotype Center). E.E. is supported by the Ruth Kirschstein National Research Award (F32 HL090258). We are grateful to the members of the Hotamisligil lab, J. Chen and R. Bachman for their scientific input and contributions, to A. Onur for technical assistance, to R. Foote and K. Gilbert for administrative support, to D. Mangelsdorf (University of Texas Southwestern) for TK-LXRE-X3luc reporter and Nr1h3−/− mice, and A. Edgar (Fournier) for the ACAT inhibitor. The pGEX-aP2-LM (R126L, Y128F) plasmid was a generous gift from D. Bernlohr (University of Minnesota).

Author information

E.E. developed the hypothesis, designed and performed the bulk of the experiments, analyzed all data and wrote the manuscript; V.R.B. contributed to the in vivo studies; J.R.M. contributed to the in vitro studies and conducted data analysis, K.N.C. and M.E.S. contributed to the in vitro studies; L.M., M.M.W. and S.M.W. contributed to the analysis of lipidomic data; S.F. and M.F.L. contributed to the analysis of in vivo data and assisted with writing; and G.S.H. developed the hypothesis, designed and analyzed all data, wrote the manuscript and supervised the project and the peer review process.

Correspondence to Gökhan S Hotamisligil.

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Competing interests

G.S.H. is on the scientific advisory board of Syndexa Pharmaceuticals. M.M.W. and S.M.W. work for Lipomics, an organization for profit.

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Erbay, E., Babaev, V., Mayers, J. et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med 15, 1383–1391 (2009).

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