Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice.

Two hypercholesterolemic mouse models, the apo-E-deficient mouse (Apoe(-/-)) and the LDL receptor-deficient mouse (Ldlr(-/-)), have been used extensively as animal models of atherogenesis. Total plasma cholesterol levels in chow-fed Apoe(-/-) mice are much higher than in Ldlr(-/-) mice. In a recent study, we managed to even-up the cholesterol levels in Apoe(-/-) mice and Ldlr(-/-) mice by making both models homozygous for the Apob(100) (apo B-100-only) allele. On a chow diet, apo-E-deficient apo B-100-only mice (Apoe(-/-)Apob(100/100)) and LDL receptor-deficient apo B-100-only mice (Ldlr(-/-)Apob(100/100)) had similar total plasma cholesterol levels ( approximately 300 mg/dL). The plasma of Ldlr(-/-)Apob(100/100) mice contained large numbers of small lipoproteins, whereas the plasma of Apoe(-/-)Apob(100/100) mice contained much lower levels of much larger lipoproteins. Interestingly, the Ldlr(-/-)Apob(100/100) mice developed far more extensive atherosclerotic lesions than the Apoe(-/-)Apob(100/100) mice. The finding of substantially more atherosclerosis in Ldlr(-/-)Apob(100/100) mice than in Apoe(-/-)Apob(100/100) mice, despite nearly identical cholesterol levels, suggests that large numbers of small apo B-100-containing lipoproteins are far more atherogenic than lower numbers of large apo B-100-containing lipoproteins.