Influence of apolipoprotein E genotype and dietary α-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice

Jofre-Monseny, Laia; Huebbe, Patricia; Stange, Inken; Boesch-Saadatmandi, Christine; Frank, Jan; Jackson, Kim G.; Minihane, Anne‐Marie; Rimbach, Gerald

doi:10.1017/s000711450788634x

Cited by 15 publications

(12 citation statements)

References 62 publications

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“…This would result in lower tissue α‐TOH, but potentially higher levels in the circulation. This is in line with our recent observations in apoE transgenic mice where significantly lower α‐TOH tissue levels were found in the lung of apoE4 compared with apoE3 mice although plasma α‐TOH concentrations were similar between the two genotypes 54. These data suggest that plasma vitamin E levels may not necessarily display peripheral vitamin E tissue status and may therefore be of limited validity.…”

Section: Apoe Genotype and Vitamin E Statussupporting

confidence: 90%

Implications of apolipoprotein E genotype on inflammation and vitamin E status

Huebbe

Lodge

Rimbach

2010

Molecular Nutrition Food Res

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In Western societies the apolipoprotein E4 (apoE4) genotype is associated with increased morbidity and mortality and represents a significant risk factor for cardiovascular and Alzheimer's disease. In a recent study we observed significantly lower tissue alpha-tocopherol (alpha-TOH) concentrations in apoE4 compared with apoE3 mice. Furthermore, genes encoding for proteins involved in peripheral alpha-TOH transport and degradation were affected by the apoE genotype. Thus, the apoE4 genotype may be associated with lower vitamin E retention in peripheral tissues. This is possibly related to an altered lipoprotein metabolism including increased alpha-TOH retention in LDL, a decreased expression of lipoprotein receptors and impaired cellular vitamin E delivery system, and a greater intracellular degradation of tocopherols in the apoE4 genotype. An increasing number of studies in cultured cells, transgenic mice and human volunteers indicate a more pro-inflammatory state associated with the apoE4 allele. In apoE4 macrophages there is an enhanced transactivation of the key redox sensitive transcription factor NF-kappaB accompanied by a higher production of pro-inflammatory molecules (tumor necrosis factor alpha, interleukin 1beta, macrophage inflammatory protein 1-alpha) and a lower production of anti-inflammatory interleukin 10, as compared with apoE3 macrophages. Both tissue vitamin E retention and biomarkers of chronic inflammation may be affected by the apoE genotype.

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Section: Apoe Genotype and Vitamin E Statussupporting

confidence: 90%

Implications of apolipoprotein E genotype on inflammation and vitamin E status

Huebbe

Lodge

Rimbach

2010

Molecular Nutrition Food Res

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“…However, more recent evidence demonstrates the multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk may be in large part due to an impact on oxidative status or the immunomodulatory/ antiinflammatory properties of apoE (13). An increasing number of studies in cell lines (19)(20)(21), targeted replacement rodents (19,22), and human volunteers (23,24) indicate higher oxidative stress and a more proinflammatory state associated with the «4 allele. Furthermore, the apo «4 allele may be associated with impairment of endothelium-dependent arterial dilation (25,26).…”

Section: Introductionmentioning

confidence: 99%

Serum Lipid and Blood Pressure Responses to Quercetin Vary in Overweight Patients by Apolipoprotein E Genotype

Egert

Boesch-Saadatmandi

Wolffram

et al. 2010

The Journal of Nutrition

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172

109

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Our objective was to examine the effect of a quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of 93 overweight-obese volunteers aged 25-65 y with metabolic syndrome traits in relation to apolipoprotein (apo) E genotype. Participants were randomized to receive 150 mg/d quercetin in a double-blinded, placebo-controlled, crossover trial with 6-wk treatment periods separated by a 5-wk washout period. Retrospectively, 5 apoE genotype variants were found (epsilon2/epsilon3, n = 3; epsilon3/epsilon3, n = 60; epsilon3/epsilon4, n = 23; epsilon2/epsilon4, n = 4; and epsilon4/epsilon4, n = 3). Participants were classified into the following 3 apoE phenotypes: apoE2 (n = 3), apoE3 (n = 60), and apoE4 (n = 26). Data were analyzed for apoE3 and apoE4 subgroups. Quercetin decreased systolic blood pressure by 3.4 mm Hg (P < 0.01) in the apoE3 group, whereas no significant effect was observed in the apoE4 group. Quercetin decreased serum HDL cholesterol (P < 0.01) and apoA1 (P < 0.01) and increased the LDL:HDL cholesterol ratio (P < 0.05) in the apoE4 subgroup, whereas the apoE3 subgroup had no significant changes in these variables. Quercetin significantly decreased plasma oxidized LDL and tumor necrosis factor-alpha in the apoE3 and apoE4 groups, whereas no significant inter-group differences were found. Serum C-reactive protein and nutritional status (body weight, waist circumference, fat mass, fat-free mass) were unaffected compared with placebo. In conclusion, quercetin exhibited blood pressure-lowering effects in overweight-obese carriers of the apo epsilon3/epsilon3 genotype but not in carriers of the epsilon4 allele. Furthermore, quercetin supplementation resulted in a reduction in HDL cholesterol and apoA1 in apo epsilon4 carriers.

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“…MT exhibits antioxidant (Miles et al 2000) and antiinflammatory properties (Inoue et al 2009). We have previously shown that the APOE4 genotype is associated with an altered inflammatory response ) and differences in the cellular oxidant/antioxidant status (Dietrich et al 2005;Jofre-Monseny et al 2008a;Huebbe et al 2007) in cultured cells, mice and humans. These differences in the inflammatory and oxidant/antioxidant status between the two genotypes may be partly related to differences in metallothionein levels.…”

Section: Discussionmentioning

confidence: 98%

Apolipoprotein E genotype affects tissue metallothionein levels: studies in targeted gene replacement mice

et al. 2012

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The apolipoprotein E (APOE) genotype is an important risk factor for ageing and age-related diseases. The APOE4 genotype (in contrast to APOE3) has been shown to be associated with oxidative stress and chronic inflammation. Metallothioneins (MT) exhibit antioxidant and anti-inflammatory activity, and MT overexpression has been shown to increase lifespan in mice. Interactions between APOE and MT, however, are largely unknown. Hence, we determined the effect of the APOE4 versus APOE3 genotype on MT levels in targeted gene replacement mice. APOE4 versus APOE3 mice exhibited significantly lower hepatic MT1 and MT2 mRNA as well as lower MT protein levels. The decrease in hepatic MT protein levels in APOE4 as compared to APOE3 mice was accompanied by lower nuclear Nrf1, a protein partly controlling MT gene expression. Cell culture experiments using hepatocytes identified allyl-isothiocyanate (AITC) as a potent MT inductor in vitro. Therefore, we supplemented APOE3 and APOE4 mice with AITC. However, AITC (15 mg/kg b.w.) could only partly correct for decreased MT1 and MT2 gene expression in APOE4 mice in vivo. Furthermore, cholesterol significantly decreased both Nrf1 and MT mRNA levels in Huh7 cells indicating that differences in MT gene expression between the two genotypes could be related to differences in hepatic cholesterol concentrations. Overall, present data suggest that the APOE genotype is an important determinant of tissue MT levels in mice and that MT gene expression may be impaired by the APOE4 genotype.

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Influence of apolipoprotein E genotype and dietary α-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice

Cited by 15 publications

References 62 publications

Implications of apolipoprotein E genotype on inflammation and vitamin E status

Implications of apolipoprotein E genotype on inflammation and vitamin E status

Serum Lipid and Blood Pressure Responses to Quercetin Vary in Overweight Patients by Apolipoprotein E Genotype

Apolipoprotein E genotype affects tissue metallothionein levels: studies in targeted gene replacement mice

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