Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice

The low density lipoprotein receptor (LDLR) plays a major role in regulatio n of plasma cholesterol levels as a ligand for apolipoprotein B-100 and apo lipoprotein E (apoE), Consequently, LDLR-deficient mice fed a Western-type diet develop significant hypercholesterolemia and atherosclerosis. ApoE not only mediates uptake of atherogenic lipoproteins via the LDLR and other ce ll-surface receptors, but also directly inhibits atherosclerosis, In this s tudy, we examined the hypothesis that coexpression of the LDLR and apoE wou ld have greater effects than either one alone on plasma cholesterol levels and the development of atherosclerosis in LDLR-deficient mice. LDLR-deficie nt mice fed a Western-type diet for 10 weeks were injected with recombinant adenoviral vectors encoding the genes for human LDLR, human apoE3, both LD LR and apoE3, or lacZ (control), Plasma lipids were analyzed at several tim e points after vector injection. Six weeks after injection, mice were analy zed for extent of atherosclerosis by two independent methods. As expected, LDLR expression alone induced a significant reduction in plasma cholesterol due to reduced VL:DL and LDL cholesterol levels, whereas overexpression of apoE alone did not reduce plasma cholesterol levels. When the LDLR and apo E were coexpressed in this model, the effects on plasma cholesterol levels were no greater than with expression of the LDLR alone. However, coexpressi on did result in a substantial increase in large apoE-rich HDL particles. I n addition, although the combination of cholesterol reduction and apoE expr ession significantly reduced atherosclerosis, its effects were no greater t han with expression of the LDLR or apoE alone. In summary, in this LDLR-def icient mouse model fed a Western-type diet, there was no evidence of an add itive effect of expression of the LDLR and apoE on cholesterol reduction or atherosclerosis. - Kawashiri, M-a., Y. Zhang, D. Usher, M. Reilly, E. Pure , and D. J. Rader. Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice.