Short communicationImpact of apolipoprotein E genotype and dietary quercetin on paraoxonase 1 status in apoE3 and apoE4 transgenic mice
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)
- et al.
Quercetin up-regulates paraoxonase 1 gene expression with concomitant protection against LDL oxidation
Biochem Biophys Res Commun
(2009) - et al.
Tissue distribution of quercetin in pigs after long-term dietary supplementation
J Nutr
(2008) - et al.
The paraoxonase gene family and atherosclerosis
Free Radic Biol Med
(2005) - et al.
High C-reactive protein and low paraoxonase1 in diabetes as risk factors for coronary heart disease
Atherosclerosis
(2006) - et al.
Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells
Atherosclerosis
(2009) - et al.
Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway
Atherosclerosis
(2010) - et al.
Impact of apoE genotype on oxidative stress, inflammation and disease risk
Mol Nutr Food Res
(2008)
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