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Publication
Macrophage-specific transgenic expression of cholesteryl ester hydrolase
significantly reduces atherosclerosis and lesion necrosis in Ldlr mice.
Authors Zhao B, Song J, Chow WN, St Clair RW, Rudel LL, Ghosh S
Submitted By Submitted Externally on 7/27/2017
Status Published
Journal The Journal of clinical investigation
Year 2007
Date Published
Volume : Pages 117 : 2983 - 92
PubMed Reference 17885686
Abstract Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to
atherosclerotic plaque formation, occurs as a result of imbalance between the
cholesterol influx and efflux pathways. While the uptake, or influx, of modified
lipoproteins is largely unregulated, extracellular acceptor-mediated free
cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE.
We previously identified and cloned a neutral CE hydrolase (CEH) from human
macrophages and demonstrated its role in cellular CE mobilization. In the
present study, we examined the hypothesis that macrophage-specific
overexpression of CEH in atherosclerosis-susceptible Ldlr(-/-) mice will result
in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing
this CEH specifically in the macrophages (driven by scavenger receptor
promoter/enhancer) were developed and crossed into the Ldlr(-/-) background
(Ldlr(-/-)CEHTg mice). Macrophage-specific overexpression of CEH led to a
significant reduction in the lesion area and cholesterol content of high-fat,
high-cholesterol diet-induced atherosclerotic lesions. The lesions from
Ldlr(-/-)CEHTg mice did not have increased FC, were less necrotic, and contained
significantly higher numbers of viable macrophage foam cells. Higher
CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall
bladder bile and feces in vivo. These studies demonstrate that by enhancing
cholesterol efflux and reverse cholesterol transport, macrophage-specific
overexpression of CEH is antiatherogenic.






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