A Macrophage Sterol-Responsive Network Linked to Atherogenesis

Cholesteryl ester accumulation by macrophages is a critical early event in atherogenesis. To test the hypothesis that sterol loading promotes foam cell formation and vascular disease by perturbing a network of interacting proteins, we used a global approach to identify proteins that are differential...

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Bibliographic Details
Published in:Cell metabolism 2010-02, Vol.11 (2), p.125-135
Main Authors: Becker, Lev, Gharib, Sina A., Irwin, Angela D., Wijsman, Ellen, Vaisar, Tomas, Oram, John F., Heinecke, Jay W.
Format: Article
Language:English
Subjects:
Animals
Apolipoproteins E - genetics
Apolipoproteins E - metabolism
Atherosclerosis - metabolism
Foam Cells - metabolism
Gene Expression Regulation
HUMDISEASE
Hypoglycemic Agents - pharmacology
Hypolipidemic Agents - pharmacology
Macrophages - metabolism
Male
Mice
Mice, Inbred C57BL
Proteins - analysis
Proteins - genetics
Proteins - metabolism
Receptors, LDL - genetics
Receptors, LDL - metabolism
Simvastatin - pharmacology
Sterols - metabolism
Thiazolidinediones - pharmacology
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Summary:Cholesteryl ester accumulation by macrophages is a critical early event in atherogenesis. To test the hypothesis that sterol loading promotes foam cell formation and vascular disease by perturbing a network of interacting proteins, we used a global approach to identify proteins that are differentially expressed when macrophages are loaded with cholesterol in vivo. Our analysis revealed a sterol-responsive network that is highly enriched in proteins with known physical interactions, established roles in vesicular transport, and demonstrated atherosclerotic phenotypes in mice. Pharmacologic intervention with a statin or rosiglitazone and use of mice deficient in LDL receptor or apolipoprotein E implicated the network in atherosclerosis. Biochemical fractionation revealed that most of the sterol-responsive proteins resided in microvesicles, providing a physical basis for the network's functional and biochemical properties. These observations identify a highly integrated network of proteins whose expression is influenced by environmental, genetic, and pharmacological factors implicated in atherogenesis. ► Cholesterol loading of macrophages alters expression of a protein network ► The sterol-responsive network localizes, in part, to microvesicles ► Genetic, pharmacological, and dietary factors link the network to atherosclerosis
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2010.01.003