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 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 (≈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.