The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

At a population level there is growing evidence for the beneficial effects of dietary flavonoids on health. However there is extensive heterogeneity in the response to increased intake, which is likely mediated via wide inter-individual variability in flavonoid absorption and metabolism. Flavonoids are extensively metabolized by phase I and II- (which occurs predominantly in the gastrointestinal tract and liver) and colonic microbial- metabolism. A number of factors, including age, gender and genotype may impact on these metabolic processes. In addition food composition and flavonoid source is likely to affect bioavailability and emerging data suggest a critical role for the microbiome. This review will focus on the current knowledge for the main sub-classes of flavonoids, including anthocyanins, flavonols, flavan-3-ols and flavanones, where there is growing evidence from prospective studies for beneficial effects on health. Identifying key factors governing metabolism, and understanding if differential capacity to metabolize these bioactive compounds impacts on health outcomes, will help establish how to optimize intakes of flavonoids for health benefits and in specific subgroups. We identify research areas which need to be addressed in order to further understand important determinants of flavonoid bioavailability and metabolism and to advance the knowledge base required to move towards the development of dietary guidelines / recommendations for flavonoids and flavonoid-rich foods

Impact of genotype on EPA and DHA status and responsiveness to increased intakes

At a population level, cardioprotective and cognitive actions of the fish oil (FO) derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been extensively demonstrated. In addition to dietary intake, which is limited for many individuals, EPA and DHA status is dependent on the efficiency of their biosynthesis from α-linolenic acid. Gender and common gene variants have been identified as influencing the rate-limiting desaturase and elongase enzymes. Response to a particular intake or status is also highly heterogeneous and likely influenced by genetic variants which impacts on EPA and DHA metabolism and tissue partitioning, transcription factor activity, or physiological end-point regulation. Here available literature relating genotype to tissue LC n-3 PUFA status and response to FO intervention is considered. It is concluded that the available evidence is relatively limited, with much of the variability unexplained, though APOE and FADS genotypes are emerging as being important. Although numerous genotype × LC-n3 PUFA × phenotype associations have been described, few have been confirmed in independent studies. A more comprehensive understanding of the genetic, physiological and behavioural modulators of EPA and DHA status and response to intervention is needed to allow refinement of current dietary LC n-3 PUFA recommendations and stratification of advice to ‘vulnerable’ and responsive subgroups

Meal fatty acids and postprandial vascular reactivity

With increasing recognition of the pivotal role of vascular dysfunction in the progression of atherosclerosis, the vasculature has emerged as an important target for dietary therapies. Recent studies have indicated that chronic fatty acid manipulation alters vascular reactivity, when measured after an overnight fast. However, individuals spend a large proportion of the day in the postprandial (non-fasted) state. Several studies have shown that high fat meals can impair endothelial function within 3-4 h, a time period often associated with peak postprandial lipaemia. Although the impact of meal fatty acids on the magnitude and duration of the postprandial lipaemic response has been extensively studied, very little is known about their impact on vascular reactivity after a meal

Impact of lipoprotein lipase gene polymorphism, S447X, on postprandial triacylglycerol and glucose response to sequential meal ingestion

Lipoprotein lipase (LPL) is a key rate-limiting enzyme for the hydrolysis of triacylglycerol (TAG) in chylomicrons and very low-density lipoprotein. Given that postprandial assessment of lipoprotein metabolism may provide a more physiological perspective of disturbances in lipoprotein homeostasis compared to assessment in the fasting state, we have investigated the influence of two commonly studied LPL polymorphisms (rs320, HindIII; rs328, S447X) on postprandial lipaemia, in 261 participants using a standard sequential meal challenge. S447 homozygotes had lower fasting HDL-C (p = 0.015) and a trend for higher fasting TAG (p = 0.057) concentrations relative to the 447X allele carriers. In the postprandial state, there was an association of the S447X polymorphism with postprandial TAG and glucose, where S447 homozygotes had 12% higher TAG area under the curve (AUC) (p = 0.037), 8.4% higher glucose-AUC (p = 0.006) and 22% higher glucose-incremental area under the curve (IAUC) (p = 0.042). A significant gene–gender interaction was observed for fasting TAG (p = 0.004), TAG-AUC (Pinteraction = 0.004) and TAG-IAUC (Pinteraction = 0.016), where associations were only evident in men. In conclusion, our study provides novel findings of an effect of LPL S447X polymorphism on the postprandial glucose and gender-specific impact of the polymorphism on fasting and postprandial TAG concentrations in response to sequential meal challenge in healthy participant

The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults

The aim of this review was to determine the impact of the fatty acid desaturase (FADS) genotype on plasma and tissue concentrations of the long-chain (LC) n-3 PUFA, including EPA and DHA, which are associated with the risk of several diet-related chronic diseases, including CVD. In addition to dietary intakes, which are low for many individuals, tissue EPA and DHA are also influenced by the rate of bioconversion from α-linolenic acid (αLNA). Δ-5 and Δ-6 desaturase enzymes, encoded for by FADS1 and FADS2 genes, are key desaturation enzymes involved in the bioconversion of essential fatty acids (αLNA and linoleic acid (LA)) to longer chained PUFA. In general, carriers of FADS minor alleles tend to have higher habitual plasma and tissue levels of LA and αLNA, and lower levels of arachidonic acid, EPA and also to a lesser extent DHA. In conclusion, available research findings suggest that FADS minor alleles are also associated with reduced inflammation and CVD risk, and that dietary total fat and fatty acid intake have the potential to modify relationships between FADS gene variants and circulating fatty acid levels. However to date, neither the size-effects of FADS variants on fatty acid status, nor the functional SNP in FADS1 and 2 have been identified. Such information could contribute to the refinement and targeting of EPA and DHA recommendations, whereby additional LC n-3 PUFA intakes could be recommended for those carrying FADS minor alleles

A transgenic Camelina sativa seed oil effectively replaces fish oil as a dietary source of eicosapentaenoic acid in mice

Background: Fish currently supplies only 40% of the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) required to allow all individuals globally to meet the minimum intake recommendation of 500 mg/d. Therefore, alternative sustainable sources are needed. Objective: The main objective was to investigate the ability of genetically engineered Camelina sativa (20% EPA) oil (CO) to enrich tissue EPA and DHA relative to an EPA-rich fish oil (FO) in mammals. Methods: Six-week-old male C57BL/6J mice were fed for 10 wk either a palm oil–containing control (C) diet or diets supplemented with EPA-CO or FO, with the C, low-EPA CO (COL), high-EPA CO (COH), low-EPA FO (FOL), and high-EPA FO (FOH) diets providing 0, 0.4, 3.4, 0.3, and 2.9 g EPA/kg diet, respectively. Liver, muscle, and brain were collected for fatty acid analysis, and blood glucose and serum lipids were quantified. The expression of selected hepatic genes involved in EPA and DHA biosynthesis and in modulating their cellular impact was determined. Results: The oils were well tolerated, with significantly greater weight gain in the COH and FOH groups relative to the C group (P < 0.001). Significantly lower (36–38%) blood glucose concentrations were evident in the FOH and COH mice relative to C mice (P < 0.01). Hepatic EPA concentrations were higher in all EPA groups relative to the C group (P < 0.001), with concentrations of 0.0, 0.4, 2.9, 0.2, and 3.6 g/100 g liver total lipids in the C, COL, COH, FOL, and FOH groups, respectively. Comparable dose-independent enrichments of liver DHA were observed in mice fed CO and FO diets (P < 0.001). Relative to the C group, lower fatty acid desaturase 1 (Fads1) expression (P < 0.005) was observed in the COH and FOH groups. Higher fatty acid desaturase 2 (Fads2), peroxisome proliferator–activated receptor α (Ppara), and peroxisome proliferator–activated receptor γ (Pparg) (P < 0.005) expressions were induced by CO. No impact of treatment on liver X receptor α (Lxra) or sterol regulatory element-binding protein 1c (Srebp1c) was evident. Conclusions: Oil from transgenic Camelina is a bioavailable source of EPA in mice. These data provide support for the future assessment of this oil in a human feeding trial

APOLIPOPROTEIN E (epsilon) genotype has a greater impact on apoB-48 than apoB-100 responses to dietary fat manipulation- insights from the SATgenε study

SCOPE: To determine the contribution of intestinally and liver-derived lipoproteins to the postprandial plasma triacylglycerol (TAG) response in APOE3/E3 and E3/E4 individuals following chronic dietary fat manipulation. METHODS AND RESULTS: In sequential order, participants (n = 12 E3/E3, n = 11 E3/E4) followed low fat (LF); high-fat, high-saturated fat (HSF); and HSF with 3.45 g/day docosahexaenoic acid (HSF-DHA) diets, each for 8 weeks. After each dietary period, an acute test meal with a macronutrient profile representative of the dietary intervention was consumed. Apolipoprotein (apo)B isoforms were determined in isolated TAG-rich lipoprotein fractions (Sf >400, Sf 60-400 and Sf 20-60) by specific ELISA. A genotype*meal/diet interaction for the Sf >400 fraction apoB-48 response (P400 particles. Fasting Sf 60-400 and 20-60 apoB-48 concentrations were also significantly higher in E4 carriers. No impact of genotype on the apoB-100 responses was evident. CONCLUSION: Our study revealed marked effects of dietary fat composition on the Sf >400 apoB-48 response and particle TAG content in E4 carriers relative to the 'wild-type' E3/E3 genotype, which suggest APOE genotype is a potential modulator of chylomicron particle synthesis. This article is protected by copyright. All rights reserved

Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention

SCOPE: People who carry the apolipoprotein E4 (APOE4) SNP have an increased risk of cardiovascular disease (CVD). Fish-oil supplementation may help in the prevention of CVD, though inter-individual differences in the response to n-3 PUFAs have been observed. We aimed to assess the impact of APOE genotype on peripheral blood mononuclear cell (PBMC) whole genome gene expression at baseline and following a fish-oil intervention.  METHODS AND RESULTS: Participants received 6 months of fish-oil supplementation containing 1800 mg of eicosapentaenoic acid and docosahexaenoic acid per day. APOE genotype and PBMC whole genome gene expression before and after supplementation were measured. We characterized the differences in gene expression profiles in carriers of APOE4 (N = 8) compared to non-carriers (N = 15). At baseline, 1320 genes were differentially expressed and the fish-oil supplementation differentially regulated 866 genes between APOE4 carriers and non-carriers. Gene set enrichment analysis showed that carriers had a higher gene expression of cholesterol biosynthesis and interferon (IFN) signaling pathways. Fish-oil supplementation reduced expression of IFN-related genes in carriers only.  CONCLUSION: The increased expression of IFN signaling and cholesterol biosynthesis pathways might explain part of the association between APOE4 and CVD. Fish-oil supplementation may particularly benefit APOE4 carriers by decreasing expression of IFN-related genes. This article is protected by copyright. All rights reserved

Polyphenols and non-alcoholic fatty liver disease: impact and mechanisms:impact and mechanisms

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic component of the metabolic syndrome and its prevalence is rapidly increasing due to its strong association with insulin resistance and obesity. At present, given that NAFLD is highly prevalent and therapies are limited, much attention is focused on identifying effective dietary strategies for the prevention and treatment of the disease. Polyphenols are a group of plant bioactive compounds whose regular consumption have been associated with a reduction in the risk of a number of metabolic disorders associated with NAFLD. Here we review the emerging and relatively consistent evidence from cell culture and rodent studies showing that select polyphenols positively modulate a variety of contributors to the NAFLD phenotype, through diverse and complementary mechanisms of action. In particular, the reduction of de novo lipogenesis (via sterol regulatory element-binding protein 1c) and increased fatty acid β-oxidation, presumably involving AMP-activated protein kinase activation, will be discussed. The indirect antioxidant and anti-inflammatory properties of polyphenols which have been reported to contribute to the amelioration of NAFLD will also be addressed. In addition to a direct study of the liver, rodent studies have provided insight into the impact of polyphenols on adipose tissue function and whole body insulin sensitivity, which are likely to in part modulate their impact on NAFLD development. Finally an overview of the limited data from clinical trials will be given along with a discussion of the dose extrapolation from animal studies to human subjects

The contribution of diet and genotype to iron status in women:a classical twin study

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04)