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

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 ± 28versus 61 ± 20 mg/g protein) and EC (102 ± 27versus 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 ± 62versus 109 ± 33 mg/g) and EC (101 ± 23versus 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.