Lipoprotein size and atherosclerosis susceptibility in Apoe-/- and Ldlr-/- mice

Abstract

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 Apob100 (apo B-100-only) allele. On a chow diet, apo-E-deficient apo B-100-only mice (Apoe-/-Apob100/100) and LDL receptor-deficient apo B-100-only mice (Ldlr-/- Apob100/100) had similar total plasma cholesterol levels (≈300 mg/dL). The plasma of Ldlr-/-Apob100/100 mice contained large numbers of small lipoproteins, whereas the plasma of Apoe-/-Apob100/100 mice contained much lower levels of much larger lipoproteins. Interestingly, the Ldlr-/-Apob100/100 mice developed far more extensive atherosclerotic lesions than the Apoe-/-Apob100/100 mice. The finding of substantially more atherosclerosis in Ldlr-/-Apob100/100 mice than in Apoe-/-Apob100/100 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.