OVEREXPRESSION OF LECITHIN, CHOLESTEROL ACYLTRANSFERASE IN TRANSGENICRABBITS PREVENTS DIET-INDUCED ATHEROSCLEROSIS

Lecithin:cholesterol acyltransferase (LCAT) is a key plasma enzyme in cholesterol and high density lipoprotein (HDL) metabolism. Transgenic rabbits overexpressing human LCAT had 15-fold greater plasma LCAT acti vity than nontransgenic control rabbits. This degree of overexpression was associated with a 6.7-fold increase in the plasma HDL cholesterol concentration in LCAT transgenic rabbits. On a 0.3% cholesterol diet, the HDL cholesterol concentrations increased from 24 +/- 1 to 39 +/- 3 mg/dl in nontransgenic control rabbits (n = 10; P < 0.05) and increa sed from 161 +/- 5 to 200 +/- 21 mg/dl (P < 0.001) in the LCAT transge nic rabbits (n = 9). Although the baseline non-HDL concentrations of c ontrol (4 +/- 3 mg/dl) and transgenic rabbits (18 +/- 4 mg/dl) were si milar, the cholesterol-rich diet raised the non-HDL cholesterol concen trations, reflecting the atherogenic very low density, intermediate de nsity, and low density lipoprotein particles observed by gel filtratio n chromatography. The non-HDL cholesterol rose to 509 +/- 57 mg/dl in controls compared with only 196 +/- 14 mg/dl in the LCAT transgenic ra bbits (P < 0.005). The differences in the plasma lipoprotein response to a cholesterol-rich diet observed in the transgenic rabbits parallel ed the susceptibility to developing aortic atherosclerosis. Compared w ith nontransgenic controls, LCAT transgenic rabbits were protected fro m diet-induced atherosclerosis with significant reductions determined by both quantitative planimetry (-86%; P < 0.003) and quantitative imm unohistochemistry (-93%; P < 0.009). Our results establish the importa nce of LCAT in the metabolism of both HDL and apolipoprotein B-contain ing lipoprotein particles with cholesterol feeding and the response to diet-induced atherosclerosis. In addition, these findings identify LC AT as a new target for therapy to prevent atherosclerosis.