title: Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice.
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.
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Seth G
authors.initials: SG
authors.lastname: Thacker
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xavier
authors.initials: X
authors.lastname: Rousset
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Safiya
authors.initials: S
authors.lastname: Esmail
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Abdalrahman
authors.initials: A
authors.lastname: Zarzour
authors.affiliation: Experimental Atherosclerosis Section, Center for Molecular, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xueting
authors.initials: X
authors.lastname: Jin
authors.affiliation: Vascular Strategies LLC, Plymouth Meeting, PA 19462.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Collins
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Maureen
authors.initials: M
authors.lastname: Sampson
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: John
authors.initials: J
authors.lastname: Stonik
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Stephen
authors.initials: S
authors.lastname: Demosky
authors.affiliation: Light Microscopy Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Malide
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Lita
authors.initials: L
authors.lastname: Freeman
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Boris L
authors.initials: BL
authors.lastname: Vaisman
authors.affiliation: Experimental Atherosclerosis Section, Center for Molecular, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Kruth
authors.affiliation: Vascular Strategies LLC, Plymouth Meeting, PA 19462.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Adelman
authors.affiliation: Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D001692:Biological Transport; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000172:deficiency* / Q000235:genetics*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D004951:Esterification; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D006801:Humans; D008079:Lipoproteins, VLDL / Q000096:biosynthesis / Q000097:blood / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D010976:Platelet Count
chemical_list: D018955:CD36 Antigens; D008079:Lipoproteins, VLDL; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase
keywords: knockout; lecithin:cholesterol acyltransferase; scavenger receptor class B member I