TYPE-III HYPERLIPOPROTEINEMIA AND SPONTANEOUS ATHEROSCLEROSIS IN MICERESULTING FROM GENE REPLACEMENT OF MOUSE APOE WITH HUMAN APOE-ASTERISK-2

To study isoform-specific effects of apolipoprotein E (apoE) in vivo, we generated mice with a human APOE2 allele in place of the mouse Apo e gene via targeted gene replacement in embryonic stem cells. Mice exp ressing human apoE2 (2/2) have virtually all the characteristics of ty pe III hyperlipoproteinemia. Their plasma cholesterol and triglyceride levels are both twice to three times those in (normolipidemic) mice t hat are expressing human apoE3 (3/3) made in an identical manner. The 2/2 mice are markedly defective in clearing beta-migrating VLDL partic les, and spontaneously develop atherosclerotic plaques, even on a regu lar diet. An atherogenic diet, high in fat and cholesterol, exacerbate s development of atherosclerosis and xanthomas in the 2/2 mice. Thus, comparisons between the 2/2 and 3/3 mice unequivocally demonstrate tha t a single amino acid difference (Arg158 Cys) in the apoE protein is s ufficient to cause type III HLP and spontaneous atherosclerosis in mic e.