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.
Highlights
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 test the hypothesis that increased expression of LCAT could overcome the cholesterol esterification defect in HDL and the free cholesterol (FC) enrichment in blood cells observed in Scarab(Ϫ/Ϫ) mice, the following lines of mice were purchased or created: 1) C57BL/6 (WT), 2) SϪL+, 3) Scarab(Ϫ/Ϫ)]×LCAT-null [Lcat(Ϫ/Ϫ)] mice (SϪLϪ), and 4) SϪL++
Results from this study reveal that modulating the expression of LCAT in mice lacking the scavenger receptor class B member I (SR-BI) receptor can have a profound effect on numerous parameters and pathways related to lipoprotein metabolism and atherosclerosis
Summary
LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice. LCAT plays a vital role in this process [1], as it is the only known plasma enzyme that esterifies free cholesterol (FC). The enrichment of FC in red blood cell (RBC) plasma membranes has been implicated in the development of atherosclerosis [13,14,15], and RBC cholesterol content has been proposed as a possible cardiovascular biomarker [15, 16]. FC on lipoproteins is known to exchange with the plasma membrane of platelets, and cholesterol enrichment has been demonstrated to promote platelet activation [20,21,22]
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