DIET-INDUCED HYPERLIPOPROTEINEMIA AND ATHEROSCLEROSIS IN APOLIPOPROTEIN E3 LEIDEN TRANSGENIC MICE

Apolipoprotein E3-Leiden (APOE3-Leiden) transgenic mice have been use d to study the effect of different cholesterol-containing diets on the remnant lipoprotein levels and composition and on the possible concur rent development of atherosclerotic plaques. On high fat/cholesterol ( HFC) diet, the high expressing lines 2 and 181 developed severe hyperc holesterolemia (up to 40 and 60 mmol/liter, respectively), whereas tri glyceride levels remained almost normal when compared with regular mou se diet. The addition of cholate increased the hypercholesterolemic ef fect of this diet. In lines 2 and 181, serum levels of apo E3-Leiden a lso increased dramatically upon cholesterol feeding (up to 107 and 300 mg/dl, respectively). In these high expressing APOE3-Leiden transgen ic mice, the increase in both serum cholesterol and apo E3-Leiden occu rred mainly in the VLDL/LDL-sized fractions, whereas a considerable in crease in large, apo E-rich HDL particles also occurred. In contrast t o the high expressing lines, the low expressing line 195 reacted only mildly upon HFC diet. On HFC diets, the high expresser APOE3-Leiden m ice developed atherosclerotic lesions in the aortic arch, the descendi ng aorta, and the carotid arteries, varying from fatty streaks contain ing foam cells to severe atherosclerotic plaques containing cholestero l crystals, fibrosis, and necrotic calcified tissue. Quantitative eval uation revealed that the atherogenesis is positively correlated with t he serum level of cholesterol-rich VLDL/LDL particles. In conclusion, with APOE3-Leiden transgenic mice, factors can be studied that influe nce the metabolism of remnant VLDL and the development of atherosclero sis.