title: Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis.
abstract: 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.
authors: Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Ebru
authors: E
authors: Erbay
authors: Vladimir R
authors: VR
authors: Babaev
authors: Jared R
authors: JR
authors: Mayers
authors: Liza
authors: L
authors: Makowski
authors: Khanichi N
authors: KN
authors: Charles
authors: Melinda E
authors: ME
authors: Snitow
authors: Sergio
authors: S
authors: Fazio
authors: Michelle M
authors: MM
authors: Wiest
authors: Steven M
authors: SM
authors: Watkins
authors: Macrae F
authors: MF
authors: Linton
authors: Gökhan S
authors: GS
authors: Hotamisligil
mesh_terms: D050197:Atherosclerosis / Q000517:prevention & control*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism*; D018384:Oxidative Stress