Editors' ChoiceMetabolism and Atherosclerosis

Lipid Liaison

See allHide authors and affiliations

Science Translational Medicine  09 Dec 2009:
Vol. 1, Issue 10, pp. 10ec37
DOI: 10.1126/scitranslmed.3000682

The endoplasmic reticulum (ER) has long been known as the central cellular site of protein synthesis, folding, and transport. In its other, auxiliary role as an integrative, regulatory hub, the ER responds to cellular stress signals or misfolded proteins, emerging as a major player in chronic metabolic diseases such as obesity and type 2 diabetes. In atherosclerotic lesions in mice and humans, macrophages containing an excess of toxic lipids show activated ER stress response pathways, yet how macrophage ER stress contributes to cardiovascular disease has been unclear. Erbay and colleagues now show that a lipid chaperone, aP2, is central to coupling toxic lipids to ER stress in both cultured macrophages and a lipid chaperone–deficient mouse model. Unexpectedly, they found that alteration of aP2 concentrations by saturated fatty acids or by a stress-attenuating chemical chaperone controlled ER stress in macrophages in vitro and in atherosclerotic lesions in vivo, revealing a previously unknown function for lipid chaperones. aP2 prevented enrichment of macrophages in desaturation products such as C16:1n7-palmitoleate, a molecule that provides relief from lipid-induced ER stress. Alleviation of ER stress, either by the use of a chemical chaperone or through the inhibition of aP2, provided enhanced protection against cell death and atherosclerosis. Whether C16:1n7 supplementation or a diet enriched with palmitoleate can confer resistance to macrophage ER stress and reduce atherosclerosis remains to be determined.

E. Erbay et al., Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat. Med. 29 November 2009 (10.1038/nm.2067) [Abstract]

Navigate This Article