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J Lipid Res. 2015 Jul;56(7):1282-95. doi: 10.1194/jlr.M048629. Epub 2015 May 11.

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice.

Author information

1
Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
2
Experimental Atherosclerosis Section, Center for Molecular, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
3
Vascular Strategies LLC, Plymouth Meeting, PA 19462.
4
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
5
Light Microscopy Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

Abstract

LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(-/-)] mice, which have a secondary defect in cholesterol esterification. Scarab(-/-)×LCAT-null [Lcat(-/-)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(-/-)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(-/-)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(-/-)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(-/-) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles.

KEYWORDS:

knockout; lecithin:cholesterol acyltransferase; scavenger receptor class B member I

PMID:
25964513
PMCID:
PMC4479333
DOI:
10.1194/jlr.M048629
[Indexed for MEDLINE]
Free PMC Article

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