期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 19, 页码 10476-10483出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1922879117
关键词
macrophages; smooth muscle cells; nanoSIMS imaging; cholesterol
资金
- National Heart, Lung, and Blood Institute [HL090553, HL087228, HL125335]
- Swiss National Centre for Competence in Research in Chemical Biology
- Swiss National Science Foundation
- Transatlantic Network Grants from the Fondation Leducq [12CVD04, 19CVD04]
- Australian Research Council Discovery Early Career Researcher Award
- Cancer Council Western Australia Early Career Investigator Grant
Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as cholesterol efflux). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist. We hypothesized that macrophages have the capacity to unload cholesterol directly onto adjacent cells. To test this hypothesis, we used methyl-beta-cyclodextrin (M beta CD) to load mouse peritoneal macrophages with [C-13]cholesterol. We then plated the macrophages (in the absence of serum or HDL) onto smooth muscle cells (SMCs) that had been metabolically labeled with [N-15]choline. After incubating the cells overnight in the absence of HDL or serum, we visualized C-13 and N-15 distribution by nanoscale secondary ion mass spectrometry (NanoSIMS). We observed substantial C-13 enrichment in SMCs that were adjacent to [C-13]cholesterol-loaded macrophages-including in cytosolic lipid droplets of SMCs. In follow-up studies, we depleted accessible cholesterol from the plasma membrane of [C-13]cholesterol-loaded macrophages with M beta CD before plating the macrophages onto the SMCs. After an overnight incubation, we again observed substantial C-13 enrichment in the SMCs adjacent to macrophages. Thus, macrophages transfer cholesterol to adjacent cells in the absence of serum or HDL. We suspect that macrophages within tissues transfer cholesterol to adjacent cells, thereby contributing to the ability to unload surplus cholesterol.
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