Article abstract

Nature Medicine 15, 1383 - 1391 (2009)
Published online: 29 November 2009 | Corrected online: 4 February 2010 | doi:10.1038/nm.2067

There is an Erratum (February 2010) associated with this Article.

Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis

Ebru Erbay1, Vladimir R Babaev2, Jared R Mayers1, Liza Makowski3, Khanichi N Charles1, Melinda E Snitow1, Sergio Fazio2, Michelle M Wiest4, Steven M Watkins4, MacRae F Linton2 & Gökhan S Hotamisligil1

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.

  1. Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
  2. Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
  3. Duke University Medical Center, Sarah W. Stedman Nutrition Center, Chapel Hill, North Carolina, USA.
  4. Lipomics Technologies, West Sacramento, California, USA.

Correspondence to: Gökhan S Hotamisligil1 e-mail:

* 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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