TARGETED REPLACEMENT OF THE MOUSE APOLIPOPROTEIN-E GENE WITH THE COMMON HUMAN APOE3 ALLELE ENHANCES DIET-INDUCED HYPERCHOLESTEROLEMIA AND ATHEROSCLEROSIS

Apolipoprotein (apo) E, a constituent of several lipoproteins, is a li gand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. W e have use a gene replacement strategy to generate mice that express t he human apoE3 isoform in place of the mouse protein. The levels of ap oE mRNA in various tissues are virtually the same in the human apoE3 h omozygous (3/3) mice and their littermates having the wild type mouse allele (+/+). Total cholesterol and triglyceride levels in fasted plas ma from the 3/3 mice were not different from those in the +/+ mice, wh en maintained on a normal (low fat) chow diet. We found, however, nota ble differences in the distribution of plasma lipoproteins and apo-lip oprotein E between the two groups: beta-migrating lipoproteins and pla sma apoB100 levels are decreased in the 3/3 mice, and the apoE distrib ution is shifted from high density lipoproteins to larger lipoprotein particles. In addition, the fractional catabolic rate of exogenously a dministered remnant particles without apoE was 6-fold slower in the 3/ 3 mice compared with the +/+ mice. When the 3/3 and +/+ animals were f ed a high fat/high cholesterol diet, the 3/3 animals responded with a dramatic increase (5-fold) in total cholesterol compared with the +/mice (1.5-fold), and after 12 weeks on this same diet the 3/3 animals developed significantly (at least 13-fold) larger atherosclerotic plaq ues in the aortic sinus area than the +/+ animals. Thus the structural differences between human APOE3 and mouse ApoE proteins are sufficien t to cause an increased susceptibility to dietary-induced hypercholest erolemia and atherosclerosis in the 3/3 mice.