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

Masa-Aki Kawashiri,Yuzhen Zhang,David Usher,Muredach Reilly,Ellen Puré,Daniel J Rader

doi:10.1016/s0022-2275(20)31618-7

Abstract

The low density lipoprotein receptor (LDLR) plays a major role in regulation of plasma cholesterol levels as a ligand for apolipoprotein B-100 and apolipoprotein 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 cell-surface receptors, but also directly inhibits atherosclerosis. In this study, we examined the hypothesis that coexpression of the LDLR and apoE would have greater effects than either one alone on plasma cholesterol levels and the development of atherosclerosis in LDLR-deficient mice. LDLR-deficient mice fed a Western-type diet for 10 weeks were injected with recombinant adenoviral vectors encoding the genes for human LDLR, human apoE3, both LDLR and apoE3, or lacZ (control). Plasma lipids were analyzed at several time points after vector injection. Six weeks after injection, mice were analyzed for extent of atherosclerosis by two independent methods. As expected, LDLR expression alone induced a significant reduction in plasma cholesterol due to reduced VLDL and LDL cholesterol levels, whereas overexpression of apoE alone did not reduce plasma cholesterol levels. When the LDLR and apoE were coexpressed in this model, the effects on plasma cholesterol levels were no greater than with expression of the LDLR alone. However, coexpression did result in a substantial increase in large apoE-rich HDL particles. In addition, although the combination of cholesterol reduction and apoE expression significantly reduced atherosclerosis, its effects were no greater than with expression of the LDLR or apoE alone. In summary, in this LDLR-deficient mouse model fed a Western-type diet, there was no evidence of an additive effect of expression of the LDLR and apoE on cholesterol reduction or atherosclerosis.—Kawashiri, M-a., Y. Zhang, D. Usher, M. Reilly, E. Puré, and D. J. Rader. Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice.

Highlights

The low density lipoprotein receptor (LDLR) plays a major role in regulation of plasma cholesterol levels as a ligand for apolipoprotein B-100 and apolipoprotein E
We used somatic gene transfer to test the additive effects of coexpression of the LDLR and apolipoprotein E (apoE) compared with either one alone on cholesterol metabolism and atherosclerosis in LDLR-deficient mice fed a Western-type diet
We hypothesized that hepatic gene transfer and coexpression of apoE and the LDLR in LDLR-deficient mice would result in a more substantial reduction in plasma cholesterol than either one alone

Summary

Introduction

The low density lipoprotein receptor (LDLR) plays a major role in regulation of plasma cholesterol levels as a ligand for apolipoprotein B-100 and apolipoprotein E (apoE). We examined the hypothesis that coexpression of the LDLR and apoE would have greater effects than either one alone on plasma cholesterol levels and the development of atherosclerosis in LDLR-deficient mice. The low density lipoprotein receptor (LDLR) mediates the removal of LDL and remnant lipoproteins from circulation by binding to apolipoprotein B-100 (apoB-100) and apolipoprotein E (apoE) and plays a major role in regulation of plasma cholesterol levels in humans [1]. Liver-directed expression of human LDLR using an adenoviral vector in LDLR-deficient mice on a normal chow diet transiently reduced plasma cholesterol levels to normal [3]. Overexpression of rat apoE in wild-type mice fed a high fat, high cholesterol diet reduced plasma cholesterol levels [15, 16]. ApoE-containing remnant lipoproteins have been shown to compete with LDL for binding to the LDL receptor [20]

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Conclusion