Elsevier

Atherosclerosis

Volume 211, Issue 1, July 2010, Pages 110-113
Atherosclerosis

Short communication
Impact of apolipoprotein E genotype and dietary quercetin on paraoxonase 1 status in apoE3 and apoE4 transgenic mice

https://doi.org/10.1016/j.atherosclerosis.2010.02.027Get rights and content

Abstract

Objectives

The aim of the present study was to determine hepatic paraoxonase 1 (PON1) status in response to apoE genotype and dietary quercetin supplementation in mice.

Methods and results

ApoE3 and apoE4 transgenic mice were fed semi-synthetic diets without (controls) and with quercetin (2 mg/g diet) for 6 weeks. Hepatic mRNA and protein levels of PON1 were significantly lower in apoE4 as compared to apoE3 mice. Feeding quercetin-enriched diets induced hepatic PON1 gene expression with a tendency for greater induction in apoE3 as compared to apoE4 mice. Furthermore, hepatic mRNA and protein levels of β-glucuronidase and sulfatase, both enzymes centrally involved in the deconjugation of quercetin conjugates, were lower in apoE4 vs. apoE3 mice. PPARγ (which partly controls PON1 gene expression) mRNA levels were lower in apoE4 vs. apoE3 mice.

Conclusion

We provide first evidence that PON1 is differentially regulated in response to apoE genotype.

Introduction

Apolipoprotein E (apoE) is a polymorphic multifunctional protein with three common isoforms in humans (E2, E3 and E4). ApoE3 is the most common isoform, while apoE4 carriers account for about 25% of the Caucasian population. Presence of the apoE4 allele is associated with a 40–50% higher risk of cardiovascular disease (CVD). The increased CVD burden has traditionally been attributed to higher LDL cholesterol in E4 carriers. However, there is increasing evidence demonstrating that the apoE4 allele may be associated with elevated oxidative stress and chronic inflammation [1], which may in turn contribute to the increased CVD in this subgroup.

Paraoxonase 1 (PON1) is a HDL associated serum enzyme which is mainly synthesized in the liver. PON1 may mediate anti-atherogenic properties by protecting low density lipoprotein (LDL) from oxidation [2]. PON1 deficient mice are highly susceptible towards atherosclerosis [3] whereas paraoxonase overexpression represses atherogenesis and promotes atherosclerotic plaque stability in mice [4]. PON1 status may be impaired by oxidative stress and pro-inflammatory cytokines.

Although strongly impacted by genetic, lifestyle and environmental factors, enhancement of the PON1 status by dietary factors, including flavonoids, are considered as a promising approach in CVD prevention. One important flavonoids subclass, the flavonols, and their major representative quercetin, are ubiquitously distributed in plant foods, and thus ingested in appreciable amounts with the daily diet. Quercetin has been shown to induce PON1 with concomitant protection against LDL oxidation in vitro [5]. However, little is known regarding the interaction between apoE genotype, dietary quercetin and PON1 status in vivo. Therefore, in this study we investigated the impact of the apoE genotype and a dietary quercetin supplementation on PON1 status in apoE3 and apoE4 transgenic mice.

Section snippets

Mice and diets

Six to eight week old female homozygous apoE3 and apoE4 transgenic mice ‘humanized’ for the apoE gene (initial body weight 17.8–18.6 g) were purchased from Taconic Europe (Ry, Denmark). Mice were divided into two dietary groups per genotype (n = 8 per group) and fed quercetin-enriched diets or control diets ad libitum for a period of 6 weeks. The semi-synthetic diet (ssniff Special Diets, Soest, Germany) was based on corn starch (15%), casein (20%), sucrose (33%) and butter fat (21%). Diets

Liver quercetin levels

Feeding the quercetin-supplemented diets significantly enhanced hepatic levels of quercetin and isorhamnetin both in apoE3 and apoE4 mice. Liver quercetin (nmol/g liver; apoE3: 2.41 ± 0.39; apoE4: 2.36 ± 0.57) and liver isorhamnetin concentrations (apoE3: 0.84 ± 0.07; apoE4: 0.78 ± 0.11) did not significantly differ between the quercetin-supplemented apoE3 and apoE4 transgenic mice. In non-supplemented animals liver quercetin (nmol/g liver; apoE3: 0.65 ± 0.02; apoE4: 0.64 ± 0.03) and isorhamnetin

Discussion

In the present study the apoE4 vs. apoE3 genotype was associated with decreased hepatic PON1 mRNA and protein levels. The underlying mechanism by which PON1 status is impaired in the apoE4 genotype is unclear. It has been suggested that PON1 may be impaired by oxidative stress [2], [8]. We have previously shown in humans that apoE4 carriers with elevated cholesterol levels exhibit higher plasma F2-isoprostane levels as compared to non-E4 carriers [9]. However, in our mouse study F2-isoprostane

Acknowledgements

We thank the German Ministry of Education and Science (BMBF 0313856A) and the DFG Cluster of Excellence “Inflammation at Interfaces” for financial support.

References (15)

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