Association between body composition and cardiometabolic disease risk: role of dietary fat intake and APOLIPOPROTEIN E genotype on this relationship.

Excess body weight is associated with increased mortality and risk of developing CVD. Body fat distribution is now considered a better indicator of disease risk than BMI, with central adiposity associated with dyslipidaemia and insulin resistance. Dietary modification is unquestionably important in the prevention of obesity and CVD, with the type but not the amount of dietary fat emerging as an important determinant of both diseases. Although reducing SFA intake via replacement with unsaturated fatty acids (UFA) is a key public health strategy for CVD prevention, variability in the lipid lowering response has been observed. This narrative review aims to investigate the link between adiposity and CVD risk, and the role of dietary fat composition and APOLIPOPROTEIN (APO)E genotype on this relationship. In the absence of weight loss, replacing dietary SFA with UFA reduces central adiposity and anthropometric measures, and is linked with lower total and LDL-cholesterol concentrations. However, differences in study populations and body composition techniques need to be taken into consideration. To date, only a limited number of studies have determined the role of APOE on body composition and CVD risk, but findings are inconsistent. Both APOE2 and APOE4 alleles have been correlated with adiposity related markers, and an APOE genotype-BMI interaction has been reported on fasting lipids. However, studies are often performed retrospectively leading to small sample sizes within the genotype groups. Further studies are needed to confirm the relationship between APOE genotype, adiposity and circulating CVD risk markers.

Impact of dairy fat manipulation on endothelial function and lipid regulation in human aortic endothelial cells exposed to human plasma samples: an in vitro investigation from the RESET study.

PURPOSE: Longer-term intake of fatty acid (FA)-modified dairy products (SFA-reduced, MUFA-enriched) was reported to attenuate postprandial endothelial function in humans, relative to conventional (control) dairy. Thus, we performed an in vitro study in human aortic endothelial cells (HAEC) to investigate mechanisms underlying the effects observed in vivo. METHODS: This sub-study was conducted within the framework of the RESET study, a 12-week randomised controlled crossover trial with FA-modified and control dairy diets. HAEC were incubated for 24 h with post-intervention plasma samples from eleven adults (age: 57.5 ± 6.0 years; BMI: 25.7 ± 2.7 kg/m2) at moderate cardiovascular disease risk following representative sequential mixed meals. Markers of endothelial function and lipid regulation were assessed. RESULTS: Relative to control, HAEC incubation with plasma following the FA-modified treatment increased postprandial NOx production (P-interaction = 0.019), yet up-regulated relative E-selectin mRNA gene expression (P-interaction = 0.011). There was no impact on other genes measured. CONCLUSION: Incubation of HAEC with human plasma collected after longer-term dairy fat manipulation had a beneficial impact on postprandial NOx production. Further ex vivo research is needed to understand the impact of partial replacement of SFA with unsaturated fatty acids in dairy foods on pathways involved in endothelial function.

Replacement of dietary saturated with unsaturated fatty acids is associated with beneficial effects on lipidome metabolites: a secondary analysis of a randomized trial.

BACKGROUND: The effects of replacing dietary saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) and/or polyunsaturated fatty acids (PUFAs) on the plasma lipidome in relation to the cardiometabolic disease (CMD) risk is poorly understood. OBJECTIVES: We aimed to assess the impact of substituting dietary SFAs with unsaturated fatty acids (UFAs) on the plasma lipidome and examine the relationship between lipid metabolites modulated by diet and CMD risk. METHODS: Plasma fatty acid (FA) concentrations among 16 lipid classes (within-class FAs) were measured in a subgroup from the Dietary Intervention and VAScular function (DIVAS) parallel randomized controlled trial (n = 113/195), which consisted of three 16-wk diets enriched in SFAs (target SFA:MUFA:n-6PUFA ratio = 17:11:4% total energy [TE]), MUFAs (9:19:4% TE), or a MUFA/PUFA mixture (9:13:10% TE). Similar lipidomics analyses were conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (specific case/cohorts: n = 775/1886 for type 2 diabetes [T2D], n = 551/1671 for cardiovascular disease [CVD]). Multiple linear regression and multivariable Cox models identified within-class FAs sensitive to replacement of dietary SFA with UFA in DIVAS and their association with CMD risk in EPIC-Potsdam. Elastic-net regression models identified within-class FAs associated with changes in CMD risk markers post-DIVAS interventions. RESULTS: DIVAS high-UFA interventions reduced plasma within-class FAs associated with a higher CVD risk in EPIC-Potsdam, especially SFA-containing glycerolipids and sphingolipids (e.g., diacylglycerol (20:0) z-score = -1.08; SE = 0.17; P value < 10-8), whereas they increased those inversely associated with CVD risk. The results on T2D were less clear. Specific sphingolipids and phospholipids were associated with changes in markers of endothelial function and ambulatory blood pressure, whereas higher low-density lipoprotein cholesterol concentrations were characterized by higher plasma glycerolipids containing lauric and stearic acids. CONCLUSIONS: These results suggest a mediating role of plasma lipid metabolites in the association between dietary fat and CMD risk. Future research combining interventional and observational findings will further our understanding of the role of dietary fat in CMD etiology. This trial was registered in ClinicalTrials.gov as NCT01478958.

Chronic consumption of probiotics, oats, and apples has differential effects on postprandial bile acid profile and cardiometabolic disease risk markers compared with an isocaloric control (cornflakes): a randomized trial.

BACKGROUND: Dietary components that impact the gut microbiota may beneficially affect cardiometabolic health, possibly by altered bile acid metabolism. However, impacts of these foods on postprandial bile acids, gut microbiota, and cardiometabolic risk markers are unclear. OBJECTIVES: The aim of this study was to determine the chronic effects of probiotics, oats, and apples on postprandial bile acids, gut microbiota, and cardiometabolic health biomarkers. METHODS: Using an acute within chronic parallel design, 61 volunteers (mean ± SD: age 52 ± 12 y; BMI 24.8 ± 3.4 kg/m2) were randomly assigned to consume 40 g cornflakes (control), 40 g oats or 2 Renetta Canada apples each with 2 placebo capsules per day or 40 g cornflakes with 2 Lactobacillus reuteri capsules (>5 × 109 CFU) per day, for 8 wk. Fasting and postprandial serum/plasma bile acids and cardiometabolic health biomarkers, fecal bile acids, and gut microbiota composition were determined. RESULTS: At week 0, oats and apples significantly decreased postprandial serum insulin [area under the curve (AUC): 25.6 (17.4, 33.8) and 23.4 (15.4, 31.4) vs. 42.0 (33.7, 50.2) pmol/L × min and incremental AUC (iAUC): 17.8 (11.6, 24.0) and 13.7 (7.7, 19.8) vs. 29.6 (23.3, 35.8) pmol/L × min] and C-peptide responses [AUC: 599 (514, 684) and 550 (467, 632) vs. 750 (665, 835) ng/mL × min], whereas non-esterified fatty acids were increased [AUC 135 (117, 153) vs. 86.3 (67.9, 105) and iAUC 96.2 (78.8, 114) vs. 60 (42.1, 77.9) mmol/L × min] after the apples vs. control (P ≤ 0.05). Postprandial unconjugated [AUC: predicted means (95% CI) 1469 (1101, 1837) vs. 363 (-28, 754) µmol/L × min and iAUC: 923 (682, 1165) vs. 22.0 (-235, 279) µmol/L × min)] and hydrophobic [iAUC: 1210 (911, 1510) vs. 487 (168, 806) µmol/L × min] bile acid responses were increased after 8 wk probiotic intervention vs. control (P ≤ 0.049). None of the interventions modulated the gut microbiota. CONCLUSIONS: These results support beneficial effects of apples and oats on postprandial glycemia and the ability of the probiotic Lactobacillus reuteri to modulate postprandial plasma bile acid profiles compared with control (cornflakes), with no relationship evident between circulating bile acids and cardiometabolic health biomarkers.

'Raising the Pulse': The environmental, nutritional and health benefits of pulse-enhanced foods.

Diet is a key modulator of non-communicable diseases, and food production represents a major cause of environmental degradation and greenhouse gas emissions. Yet, 'nudging' people to make better food choices is challenging, as factors including affordability, convenience and taste often take priority over the achievement of health and environmental benefits. The overall 'Raising the Pulse' project aim is to bring about a step change in the nutritional value of the UK consumers' diet, and to do so in a way that leads to improved health and greater sustainability within the UK food system. To achieve our objectives, UK-specific faba bean production systems that optimise both end users' diets and environmental and economic sustainability of production will be implemented in collaboration with key stakeholders (including industry, the retail sector and government). Palatable faba bean flours will be produced and used to develop 'Raising the Pulse' food products with improved nutritional profile and environmental value. Consumer focus groups and workshops will establish attitudes, preferences, drivers of and barriers to increased consumption of such products. They will inform the co-creation of sensory testing and University-wide intervention studies to evaluate the effects of pulses and 'Raising the Pulse' foods on diet quality, self-reported satiety, nutritional knowledge, consumer acceptance and market potential. Nutrient bioavailability and satiety will be evaluated in a randomised-controlled postprandial human study. Finally, a system model will be developed that predicts changes to land use, environment, business viability, nutrition and human health after substitution of existing less nutritionally beneficial and environmentally sustainable ingredients with pulses. Government health and sustainability priorities will be addressed, helping to define policy-relevant solutions with significant beneficial supply chain economic impacts and transformed sustainable food systems to improve consumer diet quality, health and the environment.

Association between APOE Genotype with Body Composition and Cardiovascular Disease Risk Markers Is Modulated by BMI in Healthy Adults: Findings from the BODYCON Study.

Body mass index (BMI) has been suggested to play an important role in the relationship between the APOLIPOPROTEIN (APO)E genotype and cardiovascular disease (CVD) risk. Using data from the BODYCON cross-sectional study (n = 360 adults) we assessed the association between body composition and CVD risk markers according to APOE genotype, with examination of the role of BMI. In this study cohort, the APOE2/E3 group had lower fasting blood lipids than APOE4 carriers and APOE3/E3 group (p ≤ 0.01). After stratifying the group according to BMI, APOE4 carriers in the normal BMI subgroup had a higher lean mass compared with the APOE3/E3 group (p = 0.02) whereas in the overweight/obese subgroup, the android to gynoid percentage fat ratio was lower in APOE4 carriers than APOE3/E3 group (p = 0.04). Fasting lipid concentrations were only different between the APOE2/E3 and other genotype groups within the normal weight BMI subgroup (p ≤ 0.04). This finding was associated with a lower dietary fibre and a higher trans-fat intake compared with APOE4 carriers, and a lower carbohydrate intake relative to the APOE3/E3 group. Our results confirm previous reports that BMI modulates the effect of APOE on CVD risk markers and suggest novel interactions on body composition, with diet a potential modulator of this relationship.

The effects of whey proteins, their peptides and amino acids on vascular function.

Cardiovascular diseases (CVD) are a significant and growing burden on global health services, and it is now accepted that impairment of vascular function represents a major preliminary step in the development of CVD. There is considerable interest in identifying both causal factors of impaired vascular function, as well as related nutritional factors that may lower the risk of developing CVD, and food-derived bioactive peptides and amino acids have emerged as one such area. Dairy foods contain two groups of proteins, whey proteins and caseins, which represent a rich source of bioactive peptides that are released during food processing and/or digestion. These peptides have a number of physiological activities including the potential to reduce blood pressure. Research, including acute and longer-term randomised controlled trials, animal models and in vitro models has demonstrated the potential impact of dairy proteins on vascular function. The purpose of this paper is to narratively review the evidence, primarily from randomised controlled trials, examining the effects of whey proteins, their peptides and amino acids on vascular function and related issues including blood pressure. In addition, it will explore the potential underlying mechanisms responsible for these effects. It concludes that there is increasing evidence that whey proteins, and notably the bioactive peptides and amino acids released during their digestion, can have beneficial effects on aspects of vascular function and thus contribute to CVD risk reduction. It also highlights a number of beneficial effects of whey proteins including those on blood pressure, arterial stiffness, nitric oxide production and inflammation.

Impact of a food-based dietary fat exchange model for replacing dietary saturated with unsaturated fatty acids in healthy men on plasma phospholipids fatty acid profiles and dietary patterns.

PURPOSE: UK guidelines recommend dietary saturated fatty acids (SFAs) should not exceed 10% total energy (%TE) for cardiovascular disease prevention, with benefits observed when SFAs are replaced with unsaturated fatty acids (UFAs). This study aimed to assess the efficacy of a dietary exchange model using commercially available foods to replace SFAs with UFAs. METHODS: Healthy men (n = 109, age 48, SD 11 year) recruited to the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention-1 (RISSCI-1) study (ClinicalTrials.Gov n°NCT03270527) followed two sequential 4-week isoenergetic moderate-fat (34%TE) diets: high-SFA (18%TE SFAs, 16%TE UFAs) and low-SFA (10%TE SFAs, 24%TE UFAs). Dietary intakes were assessed using 4-day weighed diet diaries. Nutrient intakes were analysed using paired t-tests, fasting plasma phospholipid fatty acid (PL-FA) profiles and dietary patterns were analysed using orthogonal partial least square discriminant analyses. RESULTS: Participants exchanged 10.2%TE (SD 4.1) SFAs for 9.7%TE (SD 3.9) UFAs between the high and low-SFA diets, reaching target intakes with minimal effect on other nutrients or energy intakes. Analyses of dietary patterns confirmed successful incorporation of recommended foods from commercially available sources (e.g. dairy products, snacks, oils, and fats), without affecting participants' overall dietary intakes. Analyses of plasma PL-FAs indicated good compliance to the dietary intervention and foods of varying SFA content. CONCLUSIONS: RISSCI-1 dietary exchange model successfully replaced dietary SFAs with UFAs in free-living healthy men using commercially available foods, and without altering their dietary patterns. Further intervention studies are required to confirm utility and feasibility of such food-based dietary fat replacement models at a population level.

Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation.

BACKGROUND: In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification. METHODS: The EPIC Potsdam cohort study (European Prospective Investigation into Cancer and Nutrition) comprises 27 548 participants recruited within an age range of 35 to 65 years from the general population around Potsdam, Germany. We generated 2 disease-specific case cohorts on the basis of a fixed random subsample (n=1262) and all respective cohort-wide identified incident primary cardiovascular disease (composite of fatal and nonfatal myocardial infarction and stroke; n=551) and type 2 diabetes (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in the DIVAS randomized controlled trial (Dietary Intervention and Vascular Function; n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks. RESULTS: Sixty-nine lipids associated (false discovery rate<0.05) with at least 1 outcome (both, 8; only cardiovascular disease, 49; only type 2 diabetes, 12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes; cholesteryl esters, free fatty acids, and sphingolipids were largely cardiovascular disease specific; and several (glycero)phospholipids were type 2 diabetes specific. In addition, 19 risk-associated lipids were affected (false discovery rate<0.05) by the diets rich in unsaturated dietary FAs compared with the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased diacylglycerol(FA16:0) by 0.4 (95% CI, 0.5-0.3) SD units and increased triacylglycerol(FA22:1) by 0.5 (95% CI, 0.4-0.7) SD units. CONCLUSIONS: We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention that supports the substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.

Association between dietary saturated fat with cardiovascular disease risk markers and body composition in healthy adults: findings from the cross-sectional BODYCON study.

BACKGROUND: Diets high in saturated fatty acids (SFAs) and greater abdominal obesity are both associated with raised low-density lipoprotein cholesterol (LDL-C) concentrations, an independent cardiovascular disease (CVD) risk marker. Although reducing SFA intake is a public health strategy for CVD prevention, the role of body fat distribution on the relationship between SFA and LDL-C is unclear. Therefore, our objective was to investigate whether the association between dietary SFAs and LDL-C concentrations is related to body composition. METHODS: In the BODYCON (impact of physiological and lifestyle factors on body composition) study, 409 adults [mean age 42 ± 16 years and median BMI of 23.5 (21.5-25.9) kg/m2] underwent a measure of body composition by dual energy x-ray absorptiometry, assessment of habitual dietary intake using a 4-day weighed food diary and physical activity level using a tri-axial accelerometer. Blood pressure was measured, and a fasting blood sample was collected to determine cardiometabolic disease risk markers. Correlations between body composition, circulating risk markers and dietary macronutrients were assessed prior to multivariate regression analysis. The effect of increasing intakes of dietary SFA on outcome measures was assessed using ANCOVA after adjusting for covariates. RESULTS: Abdominal visceral adipose tissue (VAT) mass was moderately positively correlated with total cholesterol (TC), LDL-C, systolic blood pressure (SBP), diastolic blood pressure and HOMA-IR (rs = 0.25-0.44, p < 0.01). In multiple regression analysis, 18.3% of the variability in LDL-C was explained by SFA intake [% total energy (TE)], abdominal VAT mass, carbohydrate%TE and fat%TE intakes. When data were stratified according to increasing SFA%TE intakes, fasting TC, LDL-C and non-high-density lipoprotein-cholesterol were higher in Q4 compared with Q2 (p ≤ 0.03). SBP was higher in Q4 versus Q3 (p = 0.01). Android lean mass was also higher in Q3 versus Q1 (p = 0.02). Other anthropometric and CVD risk markers were not different across quartile groups. CONCLUSIONS: Although dietary SFA was found to explain 9% of the variability in LDL-C, stratification of data according to quartiles of SFA intake did not reveal a dose-dependent relationship with LDL-C concentration. Furthermore, this association appeared to be independent of abdominal obesity in this cohort. Clinical Trail registration: Trial registration: clinicaltrials.gov as NCT02658539. Registered 20 January 2016, https://clinicaltrials.gov/ct2/show/NCT02658539 .

Differential effects of single fatty acids and fatty acid mixtures on the phosphoinositide 3-kinase/Akt/eNOS pathway in endothelial cells.

SCOPE: Dietary fat composition is an important modulator of vascular function. Non-esterified fatty acids (NEFA) enriched in saturated fatty acids (SFA) are thought to reduce vascular reactivity by attenuating insulin signalling via vasodilator pathways (phosphoinositide 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS)) and enhancing signalling via pro-inflammatory pathways. METHODS: To examine the effects of fatty acids on these pathways, human aortic endothelial cells were incubated with single fatty acids, and mixtures of these fatty acids to mimic typical NEFA composition and concentrations achieved in our previous human study. RNA was extracted to determine gene expression using real-time RT-PCR and cell lysates prepared to assess protein phosphorylation by Western blotting. RESULTS: Oleic acid (OA, 100 µM) was shown to down regulate expression of the insulin receptor, PTEN and a PI3K catalytic (p110ß) and regulatory (p85α) subunit compared to palmitic, linoleic and stearic acids (P < 0.04), and promote greater eNOS phosphorylation at Ser1177. Both concentration and composition of the SFA and SFA plus n-3 polyunsaturated fatty acids (PUFA) mixtures had significant effects on genes involved in the PI3K/Akt pathway. Greater up-regulation was found with 800 than 400 µM concentration (respective of concentrations in insulin resistant and normal individuals), whereas greater down-regulation was evident with SFA plus n-3 PUFA than SFA mixture alone. CONCLUSION: Our findings provide novel insights into the modulation of the PI3K/Akt/eNOS pathway by single fatty acids and fatty acid mixtures. In particular, OA appears to promote signalling via this pathway, with further work required to determine the primary molecular site(s) of action.

Effect of fat-reformulated dairy food consumption on postprandial flow-mediated dilatation and cardiometabolic risk biomarkers compared with conventional dairy: a randomized controlled trial.

BACKGROUND: Longer-term consumption of SFA-reduced, MUFA-enriched dairy products has been reported to improve fasting flow-mediated dilatation (FMD). Yet, their impact on endothelial function in the postprandial state warrants investigation. OBJECTIVES: The aim was to compare the impact of a fatty acid (FA) modified with a conventional (control) dairy diet on the postprandial %FMD (primary outcome) and systemic cardiometabolic responses to representative meals, and retrospectively explore whether treatment effects differ by apolipoprotein E (APOE) or endothelial NO synthase (eNOS) Glu298Asp gene polymorphisms. METHODS: In a crossover-design randomized controlled study, 52 adults with moderate cardiovascular disease risk consumed dairy products [38% of total energy intake (%TE) from fat: FA-modified (target: 16%TE SFAs; 14%TE MUFAs) or control (19%TE SFAs; 11%TE MUFAs)] for 12 wk, separated by an 8-wk washout. Blood sampling and FMD measurements (0-480 min) were performed pre- and postintervention after sequential mixed meals that were representative of the assigned dairy diets (0 min, ∼50 g fat; 330 min, ∼30 g fat). RESULTS: Relative to preintervention (∆), the FA-modified dairy diet and meals (treatment) attenuated the increase in the incremental AUC (iAUC), but not AUC, for the %FMD response observed with the conventional treatment (-135 ± 69% vs. +199 ± 82% × min; P = 0.005). The ∆ iAUC, but not AUC, for the apoB response decreased after the FA-modified treatment yet increased after the conventional treatment (-4 ± 3 vs. +3 ± 3 mg/mL × min; P = 0.004). The ∆ iAUC decreased for plasma total SFAs (P = 0.003) and trans 18:1 (P < 0.0001) and increased for cis-MUFAs (P < 0.0001) following the conventional relative to the FA-modified treatment. No treatment × APOE or eNOS genotype interactions were evident for any outcome. CONCLUSIONS: This study provides novel insights into the longer-term effects of FA-modified dairy food consumption on postprandial cardiometabolic responses.

Can individual fatty acids be used as functional biomarkers of dairy fat consumption in relation to cardiometabolic health? A narrative review.

In epidemiological studies, dairy food consumption has been associated with minimal effect or decreased risk of some cardiometabolic diseases (CMD). However, current methods of dietary assessment do not provide objective and accurate measures of food intakes. Thus, the identification of valid and reliable biomarkers of dairy product intake is an important challenge to best determine the relationship between dairy consumption and health status. This review investigated potential biomarkers of dairy fat consumption, such as odd-chain, trans- and branched-chain fatty acids (FA), which may improve the assessment of full-fat dairy product consumption. Overall, the current use of serum/plasma FA as biomarkers of dairy fat consumption is mostly based on observational evidence, with a lack of well-controlled, dose-response intervention studies to accurately assess the strength of the relationship. Circulating odd-chain SFA and trans-palmitoleic acid are increasingly studied in relation to CMD risk and seem to be consistently associated with a reduced risk of type 2 diabetes in prospective cohort studies. However, associations with CVD are less clear. Overall, adding less studied FA such as vaccenic and phytanic acids to the current available evidence may provide a more complete assessment of dairy fat intake and minimise potential confounding from endogenous synthesis. Finally, the current evidence base on the direct effect of dairy fatty acids on established biomarkers of CMD risk (e.g. fasting lipid profiles and markers of glycaemic control) mostly derives from cross-sectional, animal and in vitro studies and should be strengthened by well-controlled human intervention studies.

Impact of Replacement of Individual Dietary SFAs on Circulating Lipids and Other Biomarkers of Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Humans.

Little is known of the impact of individual SFAs and their isoenergetic substitution with other SFAs or unsaturated fatty acids (UFAs) on the prevention of cardiometabolic disease (CMD). This systematic literature review assessed the impact of such dietary substitutions on a range of fasting CMD risk markers, including lipid profile, markers of glycemic control and inflammation, and metabolic hormone concentrations. Eligible randomized controlled trials (RCTs) investigated the effect of isoenergetic replacements of individual dietary SFAs for ≥14 d on ≥1 CMD risk markers in humans. Searches of the PubMed, Embase, Scopus, and Cochrane CENTRAL databases on 14 February, 2021 identified 44 RCTs conducted in participants with a mean ± SD age of 39.9 ± 15.2 y. Studies' risk of bias was assessed using the Cochrane Risk of Bias tool 2.0 for RCTs. Random-effect meta-analyses assessed the effect of ≥3 similar dietary substitutions on the same CMD risk marker. Other dietary interventions were described in qualitative syntheses. We observed reductions in LDL-cholesterol concentrations after the replacement of palmitic acid (16:0) with UFAs (-0.36 mmol/L; 95% CI: -0.50, -0.21 mmol/L; I2 = 96.0%, n = 18 RCTs) or oleic acid (18:1n-9) (-0.16 mmol/L; 95% CI: -0.28, -0.03 mmol/L; I2 = 89.6%, n = 9 RCTs), with a similar impact on total cholesterol and apoB concentrations. No effects on other CMD risk markers, including HDL-cholesterol, triacylglycerol, glucose, insulin, or C-reactive protein concentrations, were evident. Similarly, we found no evidence of a benefit from replacing dietary stearic acid (18:0) with UFAs on CMD risk markers (n = 4 RCTs). In conclusion, the impact of replacing dietary palmitic acid with UFAs on lipid biomarkers is aligned with current public health recommendations. However, owing to the high heterogeneity and limited studies, relations between all individual SFAs and biomarkers of cardiometabolic health need further confirmation from RCTs. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42020084241.

Consumption of dairy products and CVD risk: results from the French prospective cohort NutriNet-Santé.

In France, dairy products contribute to dietary saturated fat intake, of which reduced consumption is often recommended for CVD prevention. Epidemiological evidence on the association between dairy consumption and CVD risk remains unclear, suggesting either null or inverse associations. This study aimed to investigate the associations between dairy consumption (overall and specific foods) and CVD risk in a large cohort of French adults. This prospective analysis included participants aged ≥18 years from the NutriNet-Santé cohort (2009-2019). Daily dietary intakes were collected using 24-h dietary records. Total dairy, milk, cheese, yogurts, fermented and reduced-fat dairy intakes were investigated. CVD cases (n 1952) included cerebrovascular disease (n 878 cases) and CHD (n 1219 cases). Multivariable Cox models were performed to investigate associations. This analysis included 104 805 French adults (mean age at baseline 42·8 (sd 14·6) years, mean follow-up 5·5 (sd 3·0) years, i.e. 579 155 person-years). There were no significant associations between dairy intakes and total CVD or CHD risks. However, the consumption of at least 160 g/d of fermented dairy (e.g. cheese and yogurts) was associated with a reduced risk of cerebrovascular diseases compared with intakes below 57 g/d (hazard ratio = 0·81 (95 % CI 0·66, 0·98), Ptrend = 0·01). Despite being a major dietary source of saturated fats, dairy consumption was not associated with CVD or CHD risks in this study. However, fermented dairy was associated with a lower cerebrovascular disease risk. Robust randomised controlled trials are needed to further assess the impact of consuming different dairy foods on CVD risk and potential underlying mechanisms.

Circulating bile acids as a link between the gut microbiota and cardiovascular health: impact of prebiotics, probiotics and polyphenol-rich foods.

Beneficial effects of probiotic, prebiotic and polyphenol-rich interventions on fasting lipid profiles have been reported, with changes in the gut microbiota composition believed to play an important role in lipid regulation. Primary bile acids, which are involved in the digestion of fats and cholesterol metabolism, can be converted by the gut microbiota to secondary bile acids, some species of which are less well reabsorbed and consequently may be excreted in the stool. This can lead to increased hepatic bile acid neo-synthesis, resulting in a net loss of circulating low-density lipoprotein. Bile acids may therefore provide a link between the gut microbiota and cardiovascular health. This narrative review presents an overview of bile acid metabolism and the role of probiotics, prebiotics and polyphenol-rich foods in modulating circulating cardiovascular disease (CVD) risk markers and bile acids. Although findings from human studies are inconsistent, there is growing evidence for associations between these dietary components and improved lipid CVD risk markers, attributed to modulation of the gut microbiota and bile acid metabolism. These include increased bile acid neo-synthesis, due to bile sequestering action, bile salt metabolising activity and effects of short-chain fatty acids generated through bacterial fermentation of fibres. Animal studies have demonstrated effects on the FXR/FGF-15 axis and hepatic genes involved in bile acid synthesis (CYP7A1) and cholesterol synthesis (SREBP and HMGR). Further human studies are needed to determine the relationship between diet and bile acid metabolism and whether circulating bile acids can be utilised as a potential CVD risk biomarker.

Dose Dependent Effects of Fructose and Glucose on de novo Palmitate and Glycerol Synthesis in an Enterocyte Cell Model.

SCOPE: Fructose exacerbates post-prandial hypertriacylglycerolaemia; perhaps partly due to increased enterocyte de novo lipogenesis (DNL). It is unknown whether this is concentration-dependent or if fructose has a greater effect on lipid synthesis than glucose. Dose-dependent effects of fructose and glucose on DNL and de novo triacylglycerol (TAG)-glycerol synthesis are investigated in a Caco-2 cell model. METHODS AND RESULTS: Caco-2 cells are treated for 96 h with 5, 25, or 50 mM fructose or glucose, or 12.5 mM fructose/12.5 mM glucose mix. DNL is measured following addition of [13 C2 ]-acetate to apical media. Separately, [13 C6 ]-fructose and [13 C6 ]-glucose are used to measure DNL and de novo TAG-glycerol synthesis. DNL from [13 C2 ]-acetate is detected following all treatments, with greater amounts in intracellular than secreted (media) samples (all p < 0.05). DNL from [13 C6 ]-fructose and [13 C6 ]-glucose is also measurable. Intracellular synthesis is concentration-dependent for both glucose (p = 0.003) and fructose (p = 0.034) tracers and is higher with 25 mM glucose than 25 mM fructose (p = 0.025). DNL from fructose and glucose is <1%, but up to 70% of de novo TAG-glycerol is synthesized from glucose or fructose. CONCLUSION: Fructose is not a major source of DNL in Caco-2 cells but contributes substantially to de novo TAG-glycerol synthesis.

Whey-Derived Peptides at the Heart of the COVID-19 Pandemic.

The renin-angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19.