Baukje de Roos

Long‐chain n‐3 polyunsaturated fatty acids: new insights into mechanisms relating to inflammation and coronary heart disease

Evidence from observational studies, prospective cohort studies and randomized clinical intervention studies indicate that moderate doses of long‐chain n‐3 polyunsaturated fatty acids (LC n‐3 PUFA) significantly decrease risk of fatal coronary heart disease (CHD). Higher doses and longer duration of intervention may also protect from non‐fatal CHD events. The exact mechanisms through which LC n‐3 PUFA has an effect on CHD are not well established but may include a decrease in fasting and postprandial triacylglycerol levels, a decrease in arrhythmias, modulation of platelet aggregation and decreased synthesis of pro‐inflammatory agents. The mechanistic relation between LC n‐3 PUFA and inflammation has attracted great interest, and in vitro studies have revealed that these fatty acids decrease endothelial activation, affect eicosanoid metabolism (including epoxygenation pathways) and induce inflammatory resolution. However, the effects of LC n‐3 PUFA on established biomarkers of inflammation and endothelial activation in vivo are not strong. Consequently we need new and more sensitive and systemic biomarkers to reveal the effects of LC n‐3 PUFA on localized inflammatory processes.

Impact of dietary polyphenols on human platelet function: a critical review of controlled dietary intervention studies

Cardiovascular disease is a chronic disease influenced by many factors, with activated blood platelets being one of them. Platelets play a central role in the formation of plaques within blood vessels, contributing to early inflammatory events. Consumption of diets rich in plant-based products protects against the development of cardiovascular disease. Polyphenols, which are secondary plant metabolites found in a wide range of foodstuffs and beverages, may be partially responsible for these effects. Their protective properties include inhibitory effects on platelet function in vitro and in vivo. However, the bioavailability of many polyphenols is poor and it is unclear whether sufficient quantities can be obtained by dietary means to exert protective effects. Consequently, this review summarizes 25 well-controlled human intervention studies examining the effect of polyphenol-rich diets on platelet function. These studies report a huge variety of research methods, study designs, and study subjects, resulting in controversial assertions. One consistent finding is that cocoa-related products, however, have platelet-inhibiting effects when consumed in moderate amounts. To assess whether other classes of dietary polyphenols, or their metabolites, also beneficially affect platelet function requires more well-controlled intervention studies as well as the adoption of more uniform methods to assess platelet aggregation and activation.

Response of apolipoprotein E*3-Leiden transgenic mice to dietary fatty acids: combining liver proteomics with physiological data

Dietary fatty acids have a profound impact on atherosclerosis, but mechanisms are not fully understood. We studied the effects of a saturated fat diet supplemented with fish oil, trans10,cis12 conjugated linoleic acid (CLA), or elaidic acid on lipid and glucose metabolism and liver protein levels of APOE*3 Leiden transgenic mice, a model for lipid metabolism and atherosclerosis. Fish oil lowered plasma and liver cholesterol and triglycerides, plasma free fatty acids, and glucose but increased plasma insulin. CLA lowered plasma cholesterol but increased plasma and liver triglycerides, plasma β‐hydroxybutyrate, and insulin. Elaidic acid lowered plasma and liver cholesterol. Proteomics identified significant regulation of 65 cytosolic and 8‐membrane proteins. Many of these proteins were related to lipid and glucose metabolism, and to oxidative stress. Principal component analysis revealed that fish oil had a major impact on cytosolic proteins, and elaidic acid on membrane proteins. Correlation analysis between physiological and protein data revealed novel clusters of correlated variables, among which a metabolic syndrome cluster. The combination of proteomics and physiology gave new insights in mechanisms by which these dietary fatty acids regulate lipid metabolism and related pathways, for example, by altering protein levels of long‐chain acyl‐CoA thioester hydrolase and adipophilin in the liver.

Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

Dietary supplementation with cis-9,trans-11 conjugated linoleic acid and aortic stiffness in overweight and obese adults

BACKGROUND Animal studies suggest that dietary cis-9,trans-11 (c9,t11) conjugated linoleic acid (CLA) may inhibit or regress the development of atherosclerosis. The effect of CLA on atherosclerosis has not been assessed in humans. OBJECTIVE We investigated the effect of c9,t11 CLA supplementation on aortic pulse wave velocity (a marker of atherosclerosis) and on cardiovascular risk factors in overweight and obese but otherwise apparently healthy subjects. DESIGN In a double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned 401 subjects, aged 40-70 y and with a body mass index (in kg/m(2)) > or = 25, to receive either 4 g CLA/d (2.5 g c9,t11 CLA/d and 0.6 g trans-10,cis-12 CLA/d) or placebo supplements for 6 mo. Aortic pulse wave velocity, blood pressure, anthropometric characteristics, and concentrations of fasting lipid, glucose, insulin, and C-reactive protein were measured before and after supplementation. RESULTS During the intervention, mean (+/-SE) pulse wave velocity did not change in the c9,t11 CLA group (Delta0.00 +/- 0.07) compared with the placebo group (Delta0.09 +/- 0.06). There was no effect of c9,t11 CLA supplementation on blood pressure, body composition, insulin resistance, or concentrations of lipid, glucose, and C-reactive protein. CONCLUSION This study does not support an antiatherosclerotic effect or an effect on cardiovascular risk factors of c9,t11 CLA. This trial was registered at www.clinicaltrials.gov as NCT00706745.

Personalised nutrition: ready for practice?

The efficacy by which dietary interventions influence risk markers of multi-factorial diseases is mainly determined by taking population-based approaches. However, there exists considerable inter-individual variation in response to dietary interventions, and some interventions may benefit certain individuals or population subgroups more than others. This review evaluates the application of nutrigenomic technologies to further the concept of personalised nutrition, as well as the process to take personalised nutrition to the marketplace. The modulation of an individuals response is influenced by both genetic and environmental factors. Many nutrigenetics studies have attempted to explain variability in responses based on a single or a few genotypes so that a genotype may be used to define personalised dietary advice. It has, however, proven very challenging to define an individuals responsiveness to complex diets based on common genetic variations. In addition, there is a limited understanding of what constitutes an optimal response because we lack key health biomarkers and signatures. In conclusion, advances in nutrigenomics will undoubtedly further the understanding of the complex interplay between genotype, phenotype and environment, which are required to enhance the development of personalised nutrition in the future. At the same time, however, issues relating to consumer acceptance, privacy protection as well as marketing and distribution of personalised products need to be addressed before personalised nutrition can become commercially viable.The efficacy by which dietary interventions influence risk markers of multi-factorial diseases is mainly determined by taking population-based approaches. However, there exists considerable inter-individual variation in response to dietary interventions, and some interventions may benefit certain individuals or population subgroups more than others. This review evaluates the application of nutrigenomic technologies to further the concept of personalised nutrition, as well as the process to take personalised nutrition to the marketplace. The modulation of an individuals response is influenced by both genetic and environmental factors. Many nutrigenetics studies have attempted to explain variability in responses based on a single or a few genotypes so that a genotype may be used to define personalised dietary advice. It has, however, proven very challenging to define an individuals responsiveness to complex diets based on common genetic variations. In addition, there is a limited understanding of what constitutes an optimal response because we lack key health biomarkers and signatures. In conclusion, advances in nutrigenomics will undoubtedly further the understanding of the complex interplay between genotype, phenotype and environment, which are required to enhance the development of personalised nutrition in the future. At the same time, however, issues relating to consumer acceptance, privacy protection as well as marketing and distribution of personalised products need to be addressed before personalised nutrition can become commercially viable.

Addressing the inter‐individual variation in response to consumption of plant food bioactives: Towards a better understanding of their role in healthy aging and cardiometabolic risk reduction

Bioactive compounds in plant‐based foods have health properties that contribute to the prevention of age‐related chronic diseases, particularly cardiometabolic disorders. Conclusive proof and understanding of these benefits in humans is essential in order to provide effective dietary recommendations but, so far, the evidence obtained from human intervention trials is limited and contradictory. This is partly due to differences between individuals in the absorption, distribution, metabolism and excretion of bioactive compounds, as well as to heterogeneity in their biological response regarding cardiometabolic health outcomes. Identifying the main factors underlying inter‐individual differences, as well as developing new and innovative methodologies to account for such variability constitute an overarching goal to ultimately optimize the beneficial health effects of plant food bioactives for each and every one of us. In this respect, this position paper from the COST Action FA1403‐POSITIVe examines the main factors likely to affect the individual responses to consumption of plant food bioactives and presents perspectives for assessment and consideration of inter‐individual variability.

Attenuation of inflammation and cellular stress-related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knockout mice on a high-fat diet.

The development of insulin resistance in the obese is associated with chronic, low‐grade inflammation. We aimed to identify novel links between obesity, insulin resistance and the inflammatory response by comparing C57BL/6 with type I interleukin‐1 receptor knockout (IL‐1RI−/−) mice, which are protected against diet‐induced insulin resistance. Mice were fed a high‐fat diet for 16 wk. Insulin sensitivity was measured and proteomic analysis was performed on adipose, hepatic and skeletal muscle tissues. Despite an equal weight gain, IL‐1RI−/− mice had lower plasma glucose, insulin and triacylglycerol concentrations, compared with controls, following dietary treatment. The higher insulin sensitivity in IL‐1RI−/− mice was associated with down‐regulation of antioxidant proteins and proteasomes in adipose tissue and hepatic soluble epoxide hydrolase, consistent with a compromised inflammatory response as well as increased glycolysis and decreased fatty acid β‐oxidation in their muscle. Their lower hepatic triacylglycerol concentrations may reflect decreased flux of free fatty acids to the liver, decreased hepatic fatty acid‐binding protein expression and decreased lipogenesis. Correlation analysis revealed down‐regulation of classical biomarkers of ER stress in their adipose tissue, suggesting that disruption of the IL‐1RI‐mediated inflammatory response may attenuate cellular stress, which was associated with significant protection from diet‐induced insulin resistance, independent of obesity.

Blood Folate Status and Expression of Proteins Involved in Immune Function, Inflammation, and Coagulation: Biochemical and Proteomic Changes in the Plasma of Humans in Response to Long-Term Synthetic Folic Acid Supplementation

We used plasma proteomics to identify human proteins responsive to folate status. Plasma was collected from subjects treated with placebo or 1.2 mg of folic acid daily for 12 weeks in a randomized controlled trial. Homocysteine and folate were measured by immunoassay and uracil misincorporation by electrophoresis. The plasma proteome was assessed by 2-D gel electrophoresis, and proteins were identified by LC MS/MS. 5-methylTHF increased 5-fold (P = 0.000003) in response to intervention. Red cell folate doubled (P = 0.013), and lymphocyte folate increased 44% (P = 0.0001). Hcy and uracil dropped 22% (P = 0.0005) and 25% (P = 0.05), respectively. ApoE A-1, alpha-1-antichymotrypsin, antithrombin, and serum amyloid P were downregulated, while albumin, IgM C, and complement C3 were upregulated (P < 0.05). More than 60 proteins were significantly associated with folate pre- and postintervention (P < 0.01). These were categorized into metabolic pathways related to complement fixation (e.g., C1, C3, C4, Factor H, Factor 1, Factor B, clusterin), coagulation (e.g., antithrombin, alpha-1-antitrypsin, kininogen) and mineral transport (e.g., transthyretin, haptoglobin, ceruloplasmin). Low folate status pre- and post-treatment were associated with lower levels of proteins involved in activation and regulation of immune function and coagulation. Supplementation with synthetic folic acid increased expression of these proteins but did not substantially disrupt the balance of these pathways.

In vitro anti‐platelet effects of simple plant‐derived phenolic compounds are only found at high, non‐physiological concentrations

SCOPE Bioactive polyphenols from fruits, vegetables, and beverages have anti-platelet effects and may thus affect the development of cardiovascular disease. We screened the effects of 26 low molecular weight phenolic compounds on two in vitro measures of human platelet function. METHODS AND RESULTS After platelets had been incubated with one of 26 low molecular weight phenolic compounds in vitro, collagen-induced human platelet aggregation and in vitro TRAP-induced P-selectin expression (as marker of platelet activation) were assessed. Incubation of platelet-rich plasma from healthy volunteers with 100 μmol/L hippuric acid, pyrogallol, catechol, or resorcinol significantly inhibited collagen-induced platelet aggregation (all p<0.05; n≥15). Incubation of whole blood with concentrations of 100 μmol/L salicylic acid, p-coumaric acid, caffeic acid, ferulic acid, 4-hydroxyphenylpropionyl glycine, 5-methoxysalicylic acid, and catechol significantly inhibited TRAP-induced surface P-selectin expression (all p<0.05; n=10). Incubation with lower concentrations of phenolics affected neither platelet aggregation nor activation. CONCLUSION As concentrations of 100 μmol/L are unlikely to be reached in the circulation, it is doubtful whether consumption of dietary phenolics in nutritionally attainable amounts plays a major role in inhibition of platelet activation and aggregation in humans.