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 extensiv ely as animal models of atherogenesis. Total plasma cholesterol levels in c how-fed Apoe(-/-) mice are much higher than in Ldlr(-/-) t mice. In a recen t 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-1 00-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 (approximate to 300 mg/dL). The plasma of Ldlr(-/-)Apob(100/100) mice contained large numb ers of small lipoproteins, whereas the plasma of Apoc(-/-)Apob(100/100) mic e contained much lower levels of much larger lipoproteins. Interestingly, t he 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 l arge numbers of small apo B-100-containing lipoproteins are far more athero genic than lower numbers of large apo B-100-containing lipoproteins.