Genetic Variations in Atherosclerosis: "Humans to Mice" and "Mice to Humans"

Abstract

The risk of atherosclerosis in humans increases progressively in association with the three common alleles of APOE in the order APOE*2 < APOE*3 < APOE4. To investigate the mechanism behind this association, we have generated mice expressing human apoE2, apoE3 or apoE4 in place of mouse apoE. We find that apoE4 mice, but not apoE2 or apoE3 mice, develop hypercholesterolemia and atherosclerosis, when they also genetically express high levels human LDLR. In contrast, apoE2 mice, but not apoE3 and apoE4 mice, develop atherosclerosis when the expression of LDLR is genetically low. These mice with humanized apoE have uncovered an important interplay between the apoE isoforms and LDLR levels in a manner previously not suspected. We further observe that, in response to consumption of a Western type high fat diet, the mice expressing apoE4 gain body weight less than those expressing apoE3. Mice expressing apoE2 gain weight most. These findings mirror the observations in human populations that body mass index is associated with APOE genotype in the order of APOE*2 > APOE*3 > APOE4. Interestingly, although epidydimal fat tissues in the apoE4 mice are smaller, they are composed of larger adipocytes than those in apoE3 mice. Reduced expression of PPARγ and adiponectin in the fat tissues of the apoE4 mice also suggests an impaired adipocyte differentiation. Indeed, the apoE4 mice are less efficient in handling glucose overload than the apoE3 mice. Together, these data indicate that the role of apoE is not limited to lipoprotein metabolism, and that apoE is likely to be an important player in the total energy homeostasis of the body and contributes to the development of metabolic syndrome in an isoform‐dependent fashion.