EFFECT OF HUMAN APOE4 ON THE CLEARANCE OF CHYLOMICRON-LIKE LIPID EMULSIONS AND ATHEROGENESIS IN TRANSGENIC MICE

Apolipoprotein (apo) E is a ligand for lipoprotein receptors and media tes the cellular uptake of several different lipoproteins. Human apoE occurs in three allelic forms designated E2, E3, and E4. The E2 isofor m is associated with changes in lipoprotein metabolism, and the E4 iso form is associated with Alzheimer's disease and an increased risk of c oronary heart disease. In this study transgenic mice were generated to assess the effect of a sustained increase in plasma apoE4 concentrati on. The transgenic animals had three- to sixfold increases in total pl asma apoE, associated primarily with the non-high-density lipoprotein (HDL) fractions of plasma lipoproteins. In response to an atherogenic diet the transgenic mice developed hypercholesterolemia similar to tha t in nontransgenic mice but did not experience the decrease in HDL cho lesterol normally observed in this strain of C57BL/6 mice. The rate of plasma clearance of a lipid emulsion mimicking lymph chylomicrons was measured in transgenic mice expressing the human apoE4 gene and compa red with the clearance rate in nontransgenic control animals. In anima ls fed a low-fat diet the emulsion lipids were cleared significantly m ore rapidly from the plasma of transgenic than control mice. In animal s adapted to a high-fat diet, the clearance of chylomicron remnants wa s slowed markedly in both transgenic and control mice and was not sign ificantly accelerated in transgenic compared with control animals. We also investigated the effect of increasing the plasma concentration of apoE4 on the progression of atherosclerotic heart disease. The extent of fatty streak lesion formation in transgenic mice expressing apoE4 was compared with nontransgenic controls. Fatty streak lesion area in the apoE4 transgenic mice was significantly decreased compared with co ntrols. Thus, an elevated plasma concentration of human apoE4 can atte nuate murine atherogenesis by a mechanism perhaps associated with chan ges in the response of HDL to an atherogenic diet.