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J. Biol. Chem., Vol. 277, Issue 5, 3511-3519, February 1, 2002

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Lecithin:Cholesterol Acyltransferase Deficiency Increases Atherosclerosis in the Low Density Lipoprotein Receptor and Apolipoprotein E Knockout Mice^*

James W. Furbee Jr., Janet K. Sawyer, and John S. Parks

From the Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157-1040

The purpose of the present study was to test the hypothesis that lecithin:cholesterol acyltransferase (LCAT) deficiency would accelerate atherosclerosis development in low density lipoprotein (LDL) receptor (LDLr/) and apoE (apoE/) knockout mice. After 16 weeks of atherogenic diet (0.1% cholesterol, 10% calories from palm oil) consumption, LDLr/ LCAT/ double knockout mice, compared with LDLr/ mice, had similar plasma concentrations of free (FC), esterified (EC), and apoB lipoprotein cholesterol, increased plasma concentrations of phospholipid and triglyceride, decreased HDL cholesterol, and 2-fold more aortic FC (142 ± 28 versus 61 ± 20 mg/g protein) and EC (102 ± 27 versus 61 ± 27 mg/g). ApoE/ LCAT/ mice fed the atherogenic diet, compared with apoE/ mice, had higher concentrations of plasma FC, EC, apoB lipoprotein cholesterol, and phospholipid, and significantly more aortic FC (149 ± 62 versus 109 ± 33 mg/g) and EC (101 ± 23 versus 69 ± 20 mg/g) than did the apoE/ mice. LCAT deficiency resulted in a 12-fold increase in the ratio of saturated + monounsaturated to polyunsaturated cholesteryl esters in apoB lipoproteins in LDLr/ mice and a 3-fold increase in the apoE/ mice compared with their counterparts with active LCAT. We conclude that LCAT deficiency in LDLr/ and apoE/ mice fed an atherogenic diet resulted in increased aortic cholesterol deposition, likely due to a reduction in plasma HDL, an increased saturation of cholesteryl esters in apoB lipoproteins and, in the apoE/ background, an increased plasma concentration of apoB lipoproteins.

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