Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein E

TLDR

ApoE functions as a receptor ligand that clears chylomicron and VLDL remnants, and its absence is expected to lead to accumulation of cholesterol‑rich remnants that promote atherogenesis. The study aimed to generate ApoE‑deficient mice via gene targeting to test the hypothesis that apoE loss causes atherogenic cholesterol accumulation and to establish a spontaneous atherosclerosis model, with the goal of using the viable phenotype to investigate modifiers of the atherogenic process. The authors created ApoE‑deficient mice via gene targeting to serve as a model for spontaneous atherosclerosis. The ApoE‑deficient mice exhibited five‑fold hypercholesterolemia, developed foam‑cell–rich aortic lesions by 3 months, and progressed to severe coronary ostial occlusion by 8 months.

Abstract

Apolipoprotein E (apoE) is a ligand for receptors that clear remnants of chylomicrons and very low density lipoproteins. Lack of apoE is, therefore, expected to cause accumulation in plasma of cholesterol-rich remnants whose prolonged circulation should be atherogenic. ApoE-deficient mice generated by gene targeting were used to test this hypothesis and to make a mouse model for spontaneous atherosclerosis. The mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months. These spontaneous lesions progressed and caused severe occlusion of the coronary artery ostium by 8 months. The severe yet viable phenotype of the mutants should make them valuable for investigating genetic and environmental factors that modify the atherogenic process.