Interaction of PPARG Pro12Ala with dietary fat influences plasma lipids in subjects at cardiometabolic risk

The PPARγ2 gene SNP Pro12Ala has shown variable association with metabolic syndrome traits in healthy subjects. We investigated the effect of interaction between genotype and the ratio of polyunsaturated:saturated (P:S) fatty acid intake on plasma lipids in 367 White subjects aged 30-70 y at increased cardiometabolic risk, in the RISCK study. Interaction was determined after habitual diet at recruitment, at baseline after a 4-week high-SFA (HS) diet and after 24-week reference (HS), high-MUFA (HM) and low-fat (LF) diets. At recruitment, there were no significant associations between genotype and plasma lipids, however, P:S x genotype interaction influenced plasma total cholesterol (TC) (P=0.02), LDL-cholesterol (LDL-C) (P=0.002) and triglyceride (TG) (P=0.02) concentrations. At P:S ratio ≤0.33, mean TC and LDL-C concentrations in Ala12 allele carriers were significantly higher than in non-carriers (respectively P=0.003; P=0.0001). Significant trends in reduction of plasma TC (P=0.02) and TG (P=0.002) concentrations occurred with increasing P:S (respectively ≤0.33 to >0.65 and 0.34 to >0.65) in Ala12 allele carriers. There were no significant differences between carriers and non-carriers after the 4-week HS diet or 24-week interventions. Plasma TC and TG concentrations in PPARG Ala12 allele carriers decrease as P:S increases, but are not dependent on a reduction in SFA intake.

Genetic predisposition to type 2 diabetes is associated with impaired insulin secretion but does not modify insulin resistance or secretion in response to an intervention to lower dietary saturated fat

Genome-wide association studies have identified SNPs reproducibly associated with type 2 diabetes (T2D). We examined the effect of genetic predisposition to T2D on insulin sensitivity and secretion using detailed phenotyping in overweight individuals with no diagnosis of T2D. Furthermore, we investigated whether this genetic predisposition modifies the responses in beta-cell function and insulin sensitivity to a 24-week dietary intervention. We genotyped 25 T2D-associated SNPs in 377 white participants from the RISCK study. Participants underwent an IVGTT prior to and following a dietary intervention that aimed to lower saturated fat intake by replacement with monounsaturated fat or carbohydrate. We composed a genetic predisposition score (T2D-GPS) by summing the T2D risk-increasing alleles of the 25 SNPs and tested for association with insulin secretion and sensitivity at baseline, and with the change in response to the dietary intervention. At baseline, a higher T2D-GPS was associated with lower acute insulin secretion (AIRg 4% lower/risk allele, P = 0.006) and lower insulin secretion for a given level of insulin sensitivity, assessed by the disposition index (DI 5% lower/risk allele, P = 0.002), but not with insulin sensitivity (Si). T2D-GPS did not modify changes in insulin secretion, insulin sensitivity or the disposition index in response to the dietary interventions to lower saturated fat. Participants genetically predisposed to T2D have an impaired ability to compensate for peripheral insulin resistance with insulin secretion at baseline, but this does not modify the response to a reduction in dietary saturated fat through iso-energetic replacement with carbohydrate or monounsaturated fat.

The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome ‘at-risk’ population syndrome.

An obese-type human microbiota with an increased Firmicutes:Bacteroidetes ratio has been described that may link the gut microbiome with obesity and metabolic syndrome (MetS) development. Dietary fat and carbohydrate are modifiable risk factors that may impact on MetS by altering the human microbiome composition. We determined the effect of the amount and type of dietary fat and carbohydrate on faecal bacteria and short chain fatty acid (SCFA) concentrations in people ‘at risk’ of MetS.

PPARγ2 gene Pro12Ala and PPARα gene Leu162Val single nucleotide polymorphisms interact with dietary intake of fat in determination of plasma lipid concentrations

Background/Aims: The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of lipid metabolism, activated by unsaturated fatty acids. We investigated independent and interactive effects of PPARγ2 gene PPARG Pro12Ala (rs1801282) andPPARαgene PPARA Leu162Val (rs1800206) genotypes with dietary intake of fatty acids on concentrations of plasma lipids in subjects of whom 47.5% had metabolic syndrome. Methods: The RISCK study is a parallel design, randomised controlled trial. Plasma lipids were quantified at baseline after a 4-week high saturated fatty acids diet and after three parallel 24-week interventions with reference (high saturated fatty acids), high monounsaturated fatty acids and low-fat diets. Single nucleotide polymorphisms were genotyped in 466 subjects. Results: At baseline, the PPARG Ala12allele was associated with increased plasma total cholesterol (n = 378; p = 0.04), LDL cholesterol (p = 0.05) and apoB (p =0.05) after adjustment for age, gender and ethnicity. At baseline, PPARA Leu162Val × PPARG Pro12Ala genotype interaction did not significantly influence plasma lipid concentrations. After dietary intervention, gene-gene interaction significantly influenced LDL cholesterol (p =0.0002) and small dense LDL as a proportion of LDL (p = 0.005) after adjustments. Conclusions: Interaction between PPARG Pro12Ala and PPARA Leu162Valgenotypes may influence plasma LDL cholesterol concentration and the proportion as small dense LDL after a high monounsaturated fatty acids diet.

Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.

Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence

An estimated 3% of the global population are infected with hepatitis C virus (HCV), and the majority of these individuals will develop chronic liver disease. As with other chronic viruses, establishment of persistent infection requires that HCV-infected cells must be refractory to a range of pro-apoptotic stimuli. In response to oxidative stress, amplification of an outward K(+) current mediated by the Kv2.1 channel, precedes the onset of apoptosis. We show here that in human hepatoma cells either infected with HCV or harboring an HCV subgenomic replicon, oxidative stress failed to initiate apoptosis via Kv2.1. The HCV NS5A protein mediated this effect by inhibiting oxidative stress-induced p38 MAPK phosphorylation of Kv2.1. The inhibition of a host cell K(+) channel by a viral protein is a hitherto undescribed viral anti-apoptotic mechanism and represents a potential target for antiviral therapy.

Acute and long-term effects of dietary fatty acids on vascular function in health and disease

Purpose of review: Vascular function is recognized as an early and integrative marker of cardiovascular disease. While there is consistent evidence that the quantity of dietary fat has significant effects on vascular function, the differential effects of individual fatty acids is less clear. This review summarizes recent evidence from randomly controlled dietary studies on the impact of dietary fatty acids on vascular function, as determined by flow-mediated dilatation (FMD). Recent findings: Critical appraisal is given to five intervention studies (one acute, four chronic) which examined the impact of long-chain n-3 polyunsaturated fatty acid [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] on FMD. In the acute setting, a high dose of long-chain n-3 polyunsaturated fatty acid (4.9 g per 70 kg man) improved postprandial FMD significantly, compared with a saturated fatty acid-rich meal in healthy individuals. In longer-term studies, there was limited evidence for a significant effect of EPA/DHA on FMD in diseased groups. Summary: The strongest evidence for the benefits of EPA/DHA on vascular function is in the postprandial state. More evidence from randomly controlled intervention trials with foods will be required to substantiate the long-term effects of EPA/DHA, to inform public health and clinical recommendations.

Food and Health Forum meeting - nutritional approaches to cardiovascular health: workshop report

This report summarises the proceedings of a meeting held by the Food and Health Forum at the Royal Society of Medicine, London, on 12 October 2011. The objective of the meeting was to highlight nutritional strategies targeted at cardiovascular health. This included a review of the effects of various foods, nutrients and ingredients on maintenance of healthy cholesterol levels, endothelial function and blood pressure

Ethnic differences in beta-cell function, dietary intake and expression of the metabolic syndrome among UK adults of south Asian, black African-Caribbean and white-European origin at high risk of metabolic syndrome

A cross-sectional analysis of ethnic differences in dietary intake, insulin sensitivity and beta-cell function, using the intravenous glucose tolerance test (IVGTT), was conducted on 497 healthy adult participants of the ‘Reading, Imperial, Surrey, Cambridge, and Kings’ (RISCK) study. Insulin sensitivity (Si) was significantly lower in African-Caribbean (AC) and South Asian (SA) participants [IVGTT-Si; AC: 2.13 vs SA: 2.25 vs white-European (WE): 2.84 (×10−4 mL µU min)2, p < 0.001]. AC participants had a higher prevalence of anti-hypertensive therapy (AC: 19.7% vs SA: 7.5%), the most cardioprotective lipid profile [total:high-density lipoprotein (HDL); AC: 3.52 vs SA: 4.08 vs WE: 3.83, p = 0.03] and more pronounced hyperinsulinaemia [IVGTT–acute insulin response (AIR)] [AC: 575 vs SA: 428 vs WE: 344 mL/µU/min)2, p = 0.002], specifically in female participants. Intake of saturated fat and carbohydrate was lower and higher in AC (10.9% and 50.4%) and SA (11.1% and 52.3%), respectively, compared to WE (13.6% and 43.8%, p < 0.001). Insulin resistance in ACs is characterised by ‘normal’ lipid profiles but high rates of hypertension and pronounced hyperinsulinaemia.

Towards a ‘civic’ narrative: British national identity and the transformation of the British National Party

This article examines the ways in which the BNP utilises the elements of British national identity in its discourse and argues that, during Griffin's leadership, the party has made a discursive choice to shift the emphasis from an ethnic to a civic narrative. We put forward two hypotheses, 1: the modernisation of the discourse of extreme right parties in the British context is likely to be related to the adoption of a predominantly civic narrative and 2: in the context of British party competition the BNP is likely to converge towards UKIP, drawing upon elements of its perceived winning formula, i.e. a predominantly civic rhetoric of national identity. We proceed to empirically test our hypotheses by conducting a twofold comparison. First, we compare the BNP's discourse pre- and post-1999 showing the BNP's progressive adoption of a civic narrative; and second the BNP's post-1999 discourse to that of UKIP in order to illustrate their similarities in terms of civic values.

Dietary patterns and cardiovascular disease

Despite strong prospective epidemiology and mechanistic evidence for the benefits of certain micronutrients in preventing CVD, neutral and negative outcomes from secondary intervention trials have undermined the efficacy of supplemental nutrition in preventing CVD. In contrast, evidence for the positive impact of specific diets in CVD prevention, such as the Dietary Approaches to Stop Hypertension (DASH) diet, has focused attention on the potential benefits of whole diets and specific dietary patterns. These patterns have been scored on the basis of current guidelines for the prevention of CVD, to provide a quantitative evaluation of the relationship between diet and disease. Using this approach, large prospective studies have reported reductions in CVD risk ranging from 10 to 60% in groups whose diets can be variously classified as 'Healthy', 'Prudent', Mediterranean' or 'DASH compliant'. Evaluation of the relationship between dietary score and risk biomarkers has also been informative with respect to underlying mechanisms. However, although this analysis may appear to validate whole-diet approaches to disease prevention, it must be remembered that the classification of dietary scores is based on current understanding of diet-disease relationships, which may be incomplete or erroneous. Of particular concern is the limited number of high-quality intervention studies of whole diets, which include disease endpoints as the primary outcome. The aims of this review are to highlight the limitations of dietary guidelines based on nutrient-specific data, and the persuasive evidence for the benefits of whole dietary patterns on CVD risk. It also makes a plea for more randomised controlled trials, which are designed to support food and whole dietary-based approaches for preventing CVD.

Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study

Aims To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = −0.357; waist circumference: β = −0.380; body fat mass: β = −0.375) and disposition index (BMI: β = −0.215; waist circumference: β = −0.248; body fat mass: β = −0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = −0.133), acute insulin response to glucose (β = −0.148) and disposition index [β = −0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction.

Association between sucrose intake and risk of overweight and obesity in a prospective sub-cohort of EPIC-Norfolk

Objective: The objective of this study was to investigate associations between sugar intake and overweight using dietary biomarkers in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). Design: Prospective cohort study Setting: European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) in the UK, recruitment between 1993 and 1997. Subjects: 1734 participants (39 – 77 years). Sucrose intake was assessed using 7-day diaries. Baseline spot urine samples were analysed for sucrose by GC-MS. Sucrose concentration adjusted by specific gravity was used as biomarker for intake. Regression analyses were used to investigate associations between sucrose intake and risk of BMI > 25 kg/m2 after three years of follow-up. Results: After three years of follow-up, mean BMI was 26.8 kg/m2. Self-reported sucrose intake was significantly positively associated with biomarker. Associations between biomarker and BMI were positive (β=0.25; 95% CI: 0.08; 0.43), while they were inverse when using self-reported dietary data (β=-1.40; 95% CI: -1.81; -0.99). Age- and sex-adjusted OR for BMI > 25 kg/m2 in participants in the fifth vs. first quintile was 1.54 (95% CI: 1.12; 2.12; pTrend=0.003,) when using biomarker and 0.56 (95% CI: 0.40; 0.77; pTrend<0.001) with self-reported dietary data. Conclusions: Our results suggest that sucrose measured by objective biomarker but not self-reported sucrose intake is positively associated with body mass index. Future studies should consider use of objective biomarkers of sucrose intake.