LECITHIN-CHOLESTEROL ACYLTRANSFERASE OVEREXPRESSION GENERATES HYPERALPHA-LIPOPROTEINEMIA AND A NONATHEROGENIC LIPOPROTEIN PATTERN IN TRANSGENIC RABBITS

Cholesterol esterification within plasma lipoprotein particles is cata lyzed by lecithin:cholesterol acyltransferase (LCAT). The impact of th e overexpression of this enzyme on plasma concentrations of the differ ent plasma lipoproteins in an animal model expressing cholesteryl este r transfer protein was evaluated by generating rabbits expressing huma n LCAT. A 6.2-kilobase human genomic DNA construct was injected into t he pronuclei of rabbit embryos. Of the 1002 embryos that were injected , 3 founder rabbits were characterized that expressed the human LCAT g ene. As in mice and humans, the principal sites of mRNA expression in these rabbits is in the liver and brain, indicating that the regulator y elements required for tissue-specific expression among these species are similar. The alpha-LCAT activity correlated with the number of co pies of LCAT that integrated into the rabbit DNA. Compared with contro ls, the high expressor LCAT-transgenic rabbits total and high density lipoprotein (HDL) cholesterol concentrations were increased 1.5-2.5-fo ld with a 3.1-fold increase in the plasma cholesterol esterification r ate. Analysis of the plasma lipoproteins by fast protein liquid chroma tography indicates that these changes reflected an increased concentra tion of apolipoprotein E-enriched, HDL(1)-sized particles, whereas ath erogenic apolipoprotein B particles disappeared from the plasma. The c oncentrations of plasma HDL cholesterol were highly correlated with bo th human LCAT mass (r = 0.93; p = 0.001) and the log LCAT activity (r = 0.94; p < 0.001) in the transgenic rabbits. These results indicate t hat overexpression of LCAT in the presence of cholesteryl ester transf er protein leads to both hyperalphalipoproteinemia and reduced concent rations of atherogenic lipoproteins.