Sarah Egert

Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study

Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25-65 years with metabolic syndrome traits. Subjects were randomised to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period. Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l (P < 0.001) during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2.6 mmHg (P < 0.01) in the entire study group, by 2.9 mmHg (P < 0.01) in the subgroup of hypertensive subjects and by 3.7 mmHg (P < 0.001) in the subgroup of younger adults aged 25-50 years. Quercetin decreased serum HDL-cholesterol concentrations (P < 0.001), while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL, but did not affect TNF-alpha and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematology and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.

Serum lipid and blood pressure responses to quercetin vary in overweight patients by apolipoprotein E genotype.

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.

Dietary α-Linolenic Acid, EPA, and DHA Have Differential Effects on LDL Fatty Acid Composition but Similar Effects on Serum Lipid Profiles in Normolipidemic Humans

Our aim was to study the effects of increased dietary intake of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) on serum lipids and LDL fatty acid compositions. To this end, a controlled parallel study was conducted in 74 healthy normolipidemic men and women aged 19-43 y. Participants were randomly assigned to 1 of 3 interventions and consumed a total intake of 4.4 g/d ALA (ALA group), 2.2 g/d EPA (EPA group), and 2.3 g/d DHA (DHA group) for 6 wk. Fatty acid ethyl esters were incorporated into margarines, which replaced the participants normal spread. The ALA, EPA, or DHA intake led to a significant enrichment of the LDL with the respective (n-3) fatty acid. In addition, LDL EPA contents in the ALA group increased by 36% (P < 0.05) with no changes in LDL DHA. The EPA intervention led to an additional enrichment with DHA (24%; P < 0.001), whereas the DHA intervention further increased the amount of EPA (249%; P < 0.001). ALA, EPA, or DHA intake did not affect fasting serum concentrations of total and LDL cholesterol, but fasting serum triacylglycerol concentrations significantly decreased in the EPA (-0.14 mmol/L) and DHA (-0.30 mmol/L) interventions and also in the ALA intervention (-0.17 mmol/L). DHA intake significantly increased serum HDL cholesterol, whereas no changes were found with ALA or EPA intake. In conclusion, the present data support the hypothesis that isolated dietary ALA, EPA, and DHA intakes lead to differential enrichment in LDL due to interconversion. Moderate amounts of ALA, EPA, and DHA are effective in improving lipid profiles of normolipidemic humans.

Impact of n − 3 fatty acids on endothelial function: results from human interventions studies

Purpose of reviewDysfunction of the endothelium plays an integral role in atherogenesis. This review summarizes recent findings on the effects of marine [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and plant [alpha-linolenic acids (ALA)] n − 3 polyunsaturated fatty acids (PUFAs) on endothelial function in healthy individuals and in patients with cardiovascular disease (CVD) risk factors or manifest CVD. Recent findingsWe identified 33 intervention trials investigating the effects of n − 3 PUFA on fasting and/or postprandial endothelial function. In healthy individuals regular supplementation of EPA/DHA or ALA shows inconsistent results on endothelial function, whereas markers of endothelial function seem to be improved in overweight dyslipidaemic patients and type 2 diabetics. Conflicting results are observed in CVD patients. Reasons for discrepancies between the study results include the health status and age of participants, duration of supplementation, dose and fatty acid composition of the administered n − 3 PUFAs as well as methods used to assess endothelial function. SummaryIn individuals with CVD risk factors including overweight, dyslipidemia and type 2 diabetes n − 3 PUFAs may improve endothelial function. However, the evidence for a clinical efficacy is not strong enough to make final recommendations with respect to a specific dose and the duration of supplementation.

Effects of whey protein supplements on metabolism: evidence from human intervention studies

Purpose of reviewEpidemiological studies indicate that the consumption of milk and dairy products is inversely associated with a lower risk of metabolic disorders and cardiovascular diseases. In particular, whey protein seems to induce these effects because of bioactive compounds such as lactoferrin, immunoglobulins, glutamine and lactalbumin. In addition, it is an excellent source of branch chained amino acids. This review summarizes recent findings on the effects of whey protein on metabolic disorders and the musculoskeletal system. Recent findingsWe identified 25 recently published intervention trials examining chronic and/or acute effects of whey protein supplementation on lipid and glucose metabolism, blood pressure, vascular function and on the musculoskeletal system. Whey protein appears to have a blood glucose and/or insulin lowering effect partly mediated by incretins. In addition, whey protein may increase muscle protein synthesis. In contrast there are no clear-cut effects shown on blood lipids and lipoproteins, blood pressure and vascular function. For bone metabolism the data are scarce. SummaryIn summary, whey protein may affect glucose metabolism and muscle protein synthesis. However, the evidence for a clinical efficacy is not strong enough to make final recommendations with respect to a specific dose and the duration of supplementation.

APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans

The allele ε4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimers disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE ε4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE ε4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE ε4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests ε4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks.—Huebbe, P., Nebel, A., Siegert, S., Moehring, J., Boesch‐Saadatmandi, C., Most, E., Pallauf, J., Egert, S., Müller, M. J., Schreiber, S., Nöthlings, U., Rimbach, G. APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J. 25, 3262‐3270 (2011). www.fasebj.org

Effect of Quercetin on Paraoxonase 2 Levels in RAW264.7 Macrophages and in Human Monocytes––Role of Quercetin Metabolism

There is increasing evidence that the intracellular antioxidant enzyme paraoxonase 2 (PON2) may have a protective function in the prevention of atherogenesis. An enhancement of PON2 activity by dietary factors including flavonoids is therefore of interest. In the present study we determined the effect of quercetin on paraoxonase 2 levels in cultured murine macrophages in vitro and in overweight subjects with a high cardiovascular risk phenotype supplemented with 150 mg quercetin/day for 42 days in vivo. Supplementation of murine RAW264.7 macrophages in culture with increasing concentrations of quercetin (1, 10, 20 μmol/L) resulted in a significant increase in PON2 mRNA and protein levels, as compared to untreated controls. Unlike quercetin, its glucuronidated metabolite quercetin-3-glucuronide did not affect PON2 gene expression in cultured macrophages. However the methylated quercetin derivative isorhamnetin enhanced PON2 gene expression in RAW264.7 cells to similar extent like quercetin. Although supplementing human volunteers with quercetin was accompanied by a significant increase in plasma quercetin concentration, dietary quercetin supplementation did not change PON2 mRNA levels in human monocytes in vivo. Current data indicate that quercetin supplementation increases PON2 levels in cultured monocytes in vitro but not in human volunteers in vivo.

Influence of three rapeseed oil-rich diets, fortified with alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid on the composition and oxidizability of low-density lipoproteins: results of a controlled study in healthy volunteers.

Objective:To compare the individual effects of dietary α-linolenic acid (ALA), eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) on low-density lipoprotein (LDL) fatty acid composition, ex vivo LDL oxidizability and tocopherol requirement.Design, setting and subjects:A randomized strictly controlled dietary study with three dietary groups and a parallel design, consisting of two consecutive periods. Sixty-one healthy young volunteers, students at a nearby college, were included. Forty-eight subjects (13 males, 35 females) completed the study.Interventions:Subjects received a 2-week wash-in diet rich in monounsaturated fatty acids (21% energy) followed by experimental diets enriched with about 1% of energy of ALA, EPA or DHA for 3 weeks. The omega-3 (n-3) fatty acids were provided with special rapeseed oils and margarines. The wash-in diet and the experimental diets were identical, apart from the n-3 fatty acid composition and the tocopherol content, which was adjusted to the content of dienoic acid equivalents.Results:Ex vivo oxidative susceptibility of LDL was highest after the DHA diet, indicated by a decrease in lag time (−16%, P<0.001) and an increase in the maximum amount of conjugated dienes (+7%, P<0.001). The EPA diet decreased the lag time (−16%, P<0.001) and the propagation rate (−12%, P<0.01). Tocopherol concentrations in LDL decreased in the ALA group (−13.5%, P<0.05) and DHA group (−7.3%, P<0.05). Plasma contents of tocopherol equivalents significantly decreased in all three experimental groups (ALA group: −5.0%, EPA group: −5.7%, DHA group: −12.8%). The content of the three n-3 polyunsaturated fatty acid differently increased in the LDL: on the ALA diet, the ALA content increased by 89% (P<0.001), on the EPA diet the EPA content increased by 809% (P<0.001) and on the DHA diet, the DHA content increased by 200% (P<0.001). In addition, the EPA content also enhanced (without dietary intake) in the ALA group (+35%, P<0.01) and in the DHA group (+284%, P<0.001).Conclusions:Dietary intake of ALA, EPA or DHA led to a significant enrichment of the respective fatty acid in the LDL particles, with dietary EPA preferentially incorporated. In the context of a monounsaturated fatty acid-rich diet, ALA enrichment did not enhance LDL oxidizability, whereas the effects of EPA and DHA on ex vivo LDL oxidation were inconsistent, possibly in part due to further changes in LDL fatty acid composition.Sponsorship:This research was financially supported by the German Federal Ministry of Education and Research (BMBF) within the project ‘NAPUS 2000 – healthy foodstuffs from transgenic rapeseed’.

Effects of a quercetin-rich onion skin extract on 24 h ambulatory blood pressure and endothelial function in overweight-to-obese patients with (pre-)hypertension: a randomised double-blinded placebo-controlled cross-over trial

The polyphenol quercetin may prevent CVD due to its antihypertensive and vasorelaxant properties. We investigated the effects of quercetin after regular intake on blood pressure (BP) in overweight-to-obese patients with pre-hypertension and stage I hypertension. In addition, the potential mechanisms responsible for the hypothesised effect of quercetin on BP were explored. Subjects (n 70) were randomised to receive 162 mg/d quercetin from onion skin extract powder or placebo in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 6-week washout period. Before and after the intervention, ambulatory blood pressure (ABP) and office BP were measured; urine and blood samples were collected; and endothelial function was measured by EndoPAT technology. In the total group, quercetin did not significantly affect 24 h ABP parameters and office BP. In the subgroup of hypertensives, quercetin decreased 24 h systolic BP by −3·6 mmHg (P=0·022) when compared with placebo (mean treatment difference, −3·9 mmHg; P=0·049). In addition, quercetin significantly decreased day-time and night-time systolic BP in hypertensives, but without a significant effect in inter-group comparison. In the total group and also in the subgroup of hypertensives, vasoactive biomarkers including endothelin-1, soluble endothelial-derived adhesion molecules, asymmetric dimethylarginine, angiotensin-converting enzyme activity, endothelial function, parameters of oxidation, inflammation, lipid and glucose metabolism were not affected by quercetin. In conclusion, supplementation with 162 mg/d quercetin from onion skin extract lowers ABP in patients with hypertension, suggesting a cardioprotective effect of quercetin. The mechanisms responsible for the BP-lowering effect remain unclear.

Effects of Dietary α-Linolenic Acid, Eicosapentaenoic Acid or Docosahexaenoic Acid on Parameters of Glucose Metabolism in Healthy Volunteers

Aim: To investigate the effects of α-linolenic acid (ALA) and purified eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) on fasting concentrations of glucose, insulin, fructosamine, on glycosylated haemoglobin (HbA1c) and on insulin sensitivity. Methods: A randomized strictly controlled dietary study in 48 healthy volunteers (13 males, 35 females) of normal body weight (mean age 25.9 years) with three dietary groups (ALA, EPA and DHA) and a parallel design, consisting of two consecutive periods. Subjects received a 2-week wash-in diet rich in monounsaturated fatty acids followed by experimental diets enriched with equal amounts of ALA, EPA, or DHA for 3 weeks. Mean dietary intake of ALA in the ALA group was 6.0 g/day (2.5% of energy intake), mean intake of EPA in the EPA group was 2.8 g/day (1.1% of energy intake) and mean intake of DHA in the DHA group was 2.9 g/day (1.1% of energy intake). Results: Fasting serum concentrations of insulin and fructosamine and of HbA1c did not change significantly after consuming the ALA, EPA or DHA diet. Fasting serum glucose levels did not change significantly following either the ALA or DHA diet. During the EPA diet, fasting glucose concentration slightly increased by 0.15 mmol/l (p < 0.05). All measured values of all subjects were in the reference ranges for healthy adults. No effects on insulin sensitivity indicated by the HOMA insulin resistance index could be observed. Conclusions: Except for the minor effect of EPA on fasting glucose levels, the moderate amounts of dietary ALA, EPA or DHA administered in this study did not significantly affect blood concentrations of glucose, insulin, fructosamine and HbA1c in healthy normal-weight men and women over a time course of 3 weeks.