Journal
CELL METABOLISM
Volume 11, Issue 2, Pages 125-135Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2010.01.003
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Funding
- National Institutes of Health [HL030086, HL018645, HL074223, HL078527, HI092969, HL086798]
- Canadian Institutes of Health Research Fellowship Award
- Diabetes and Endocrinology Research Center
- Mass Spectrometry Resource (Department of Medicine)
- Proteome Resource (School of Medicine)
- Mass Spectrometry Core (Diabetes and Endocrinology Research Center) at the University of Washington
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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.
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