Overexpression of apolipoprotein E in transgenic mice: marked reduction in plasma lipoproteins except high density lipoprotein and resistance against diet-induced hypercholesterolemia.

Abstract

Apolipoprotein E (apoE) has a high affinity to cell-surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under the control of the metallothionein promoter were established. We found that a high expresser line produced rat apoE mainly in the liver, and the gene product was almost entirely assodated with plasma lipoproteins. The plasma level of rat apoE in homozygotes for the transgene was 17.4 mg/dl after zinc induction (vs. 4.56 mg/dl of mouse apoE in controls). In this group, plasma cholesterol and triglyceride levels were 43% and 68% reduced as compared with controls, respectively. Heterozygotes showed decreases in both lipids to a lesser extent. Gel filtration chromatography showed that lipid reduction was mainly due to decreased very low density lipoproteins (VLDL) and LDL. Especially in zinc-treated homozygotes, VLDL had almost disappeared, and a remarkable decrease in LDL and a slight decrease in high density lipoprotein were also observed. Consistently, the plasma level of apoB, a structural protein of VLDL and LDL, was 78% lower than that of controls, indicating a marked reduction in lipoproteins containing apoB. Furthermore, the transgenic mice, in contrast to controls, did not develop hypercholesterolemia when fed a high cholesterol diet. These results demonstrated that overexpression of apoE reduces plasma cholesterol and triglyceride levels and prevents diet-induced hypercholesterolemia. From dramatic and doserelated decreases in plasma lipoproteins in transgenic mice, we conclude that apoE plays a key role in plasma lipoprotein metabolism.Apolipoprotein E (apoE) is a major component ofmammalian lipoproteins along with apolipoprotein B100 (apoB100) and functions in metabolism of plasma lipoproteins through its interaction with the low density lipoprotein (LDL) receptor mainly in the liver (for a review, see ref. 1); apoE is also thought to be a specific ligand for the putative hepatic chylomicron remnant receptor (apoE receptor) (1). Expressed in many tissues, apoE plays a crucial role in transport and redistribution of lipids in peripheral tissues such as brain, peripheral nerve, and arterial wall (1). Several lines of evidence suggest that lipoproteins with several molecules of apoE have a higher affinity for LDL receptors than those without apoE (1-7). In vitro studies have shown that enrichment in apoE on very low density lipoprotein (VLDL) particles increases uptake of these lipoproteins both when cells were cultured with human VLDL that had been incubated with excess purified apoE or recombinant apoE (3,8,9) and when the transfected CHO cells overexpressing apoE were cultured with unmodified human VLDL (10). Recently, we and another group have reported that intravenous administration ofapoE causes the incorporation ofexogenous apoE onto plasma lipoproteins, enhances clearance of VLDL, and reduces the production of LDL from VLDL, resulting in a lowered plasma cholesterol l...

Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by intramuscular injection of plasmid DNA

“…5,6 These observations support the hypothesis that apoE supplementation may result in the correction of dyslipidemia. Decreased serum cholesterol levels and increased lipoprotein clearance have been detected in apoE-deficient mice after bone marrow transplantation from syngenic healthy donors.…”

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies

“…Indeed, these technologies are quite powerful and useful for the study of lipoprotein metabolism. For example, overexpression of apo E prevented the development of atherosclerosis (Shimano et al 1992). In contrast, mice lacking apo E showed spontaneous development of hypercholesterolemia and arterial lesions (Plump et al 1992, Zhang et al 1992.…”

“…Recent progress in molecular biology, such as transgenic technology, has enabled the study of specific gene function, which classical pharmacological experiments could not dissect out. Over-expression of the apo E gene in mice resulted in a decrease in cholesterol and prevention of atherosclerosis (Shimano et al 1992). Recently, there has been increased interest in the role of apo E in cholesterol metabolism, because mice lacking the apo E gene have been created by gene targeting technology.…”

Genetically Modified Animal Models for Lipoprotein Research

“…However, influences of the overexpression of apoB, apoE, and apo(a) differ between mice and rabbits. ApoE overexpression resulted in a marked decrease in non-HDL cholesterol in mice (Shimano, 1992), while in rabbits, cholesterol of LDL and HDL increased and the fractional catabolic rate of chylomicron also increased (Fan, 1998). These differences between mice and rabbits may be due to CETP activity and the expression of abobec-1 in mouse liver.…”