EXPRESSION OF HUMAN LECITHIN-CHOLESTEROL ACYLTRANSFERASE IN TRANSGENIC MICE - EFFECT OF HUMAN APOLIPOPROTEIN AI AND HUMAN APOLIPOPROTEIN AII ON PLASMA-LIPOPROTEIN CHOLESTEROL-METABOLISM

Human (Hu) lecithin-cholesterol acyltransferase (LCAT) is a key enzyme in the plasma metabolism of cholesterol. To assess the effects of inc reased plasma levels of LCAT, four lines of transgenic mice were creat ed expressing a Hu LCAT gene driven by either its natural or the mouse albumin enhancer promoter. Plasma LCAT activity increased from 1.2- t o 1.6-fold higher than that found in control mouse plasma. Lipid profi les, upon comparing HuLCAT transgenics to control animals, revealed a 20 to 60% increase in total and cholesteryl esters that were mainly pr esent in HDL. The in vivo substrate specificity of Hu LCAT was assesse d by creating animals expressing Hu apo AI + Hu LCAT (HuAI/LCAT), Hu a po AI + Hu apo AII + Hu LCAT (HuAI/AII/LCAT), and Hu apo AII + Hu LCAT (HuAII/LCAT). Plasma cholesterol was increased up to 4,2-fold in HuAI /LCAT LCAT transgenic mice and two fold in the HuAI/AII/LCAT transgeni c mice, compared with HuAI and HuAI/AII transgenic mice, HDL cholester yl ester levels were increased more than twofold in both the HuAI/LCAT and HuAI/AII/LCAT mice compared with the HuAI, HuAI/AII, and HuLCAT a nimals. The HDL particles were predominantly larger in the HuAI/LCAT a nd the HuAI/AII/LCAT mice compared with those in HuAI, HuAII/LCAT, and HuLCAT animals. The increase in LCAT activity in the HuAI/LCAT and Hu AI/AII/LCAT mice was associated with 62 and 27% reductions respectivel y, in the proportion of Hu apo AI in the pre beta-HDL fraction, when c ompared with HuAI and HuAI/AII transgenic mice. These data demonstrate that moderate increases in LCAT activity are associated with signific ant changes in lipoprotein cholesterol levels and that Hu LCAT has a s ignificant preference for HDL containing Hu apo AI.