Objective-Carriers of the PCSK9 (proprotein convertase subtilisin/kexin 9) R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease. We studied the impact of the R46L variant on lipoprotein size and composition. Approach and Results-Lipoprotein size and composition were measured by nuclear magnetic resonance spectroscopy in 2373 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. DiscussionOur study shows that carriers of the PCSK9 R46L variant are characterized by lower levels of NMR-measured atherogenic lipoproteins and subfractions compared with noncarriers. The most prominent differences based on percentage change between carriers and noncarriers were observed with IDL-P (−18%) and medium VLDL-P (−16%; Figure). The most prominent differences based on change in SD between carriers and noncarriers were observed with apolipoprotein B ( who have reported a 15% reduction in LDL-C in carriers of the PCSK9 R46L variant in the ARIC study (Atherosclerosis Risk in Communities). The effect on other parameters of the lipoprotein-lipid profile was comparable, with in both studies significant lower levels of total cholesterol and no effect on high-density lipoprotein cholesterol.In a cross-sectional study of 52 healthy subjects, PCSK9 levels were found to correlate with total cholesterol, nonhigh-density lipoprotein cholesterol, LDL-C, triglycerides, and VLDL-P and LDL-P concentrations. 4 In a subsequent multivariable regression analysis, PCSK9 levels were only related to LDL-P concentration. Interestingly, in an analysis that included the 3 LDL subfractions, PCSK9 was only associated with IDL-P. The R46L variant examined in our study has been shown to be associated with lower levels of PCSK9, 5 and therefore, we expected a similar effect on NMR lipoprotein subfractions. Our study suggests that there is not only an association between PCSK9 and IDL-P but also with other lipoprotein particles. The effect of the R46L variant on lipoproteins in our study seemed to be comparable with the results of Chasman et al, 6 who showed a significant effect of the single-nucleotide polymorphism on large LDL-P, total LDL-P, small LDL-P, IDL-P, LDL-C, total VLDL-P, and small VLDL-P. Other groups also documented the effect of different single-nucleotide The relationship between LDL-C and CVD risk is strong and consistent, but evidence suggest that LDL-P concentrations could be more closely associated with CVD risk than LDL-C. 12 Because of a possible discordance between LDL-C and LDL-P concentrations, patients with LDL-C levels on target could be at increased CVD risk attributable to high LDL-P levels. 13 The American Association of Clinical Chemistry has suggested to strive for a LDL-P concentration treatment goal of <1100 nmol/L 14 or an equivalent LDL-C level of <100 mg/dL in patients at high CVD risk according to the National Cholesterol Education Program Adult Treatment Panel III. 15As w...

Abstract Background Recent evidence suggests that the association between dietary saturated fatty acids (SFAs) and coronary artery disease risk varies according to food sources. How SFAs from butter and cheese influence HDL-mediated cholesterol efflux capacity (CEC), a key process in reverse cholesterol transport, is currently unknown. Objective In a predefined secondary analysis of a previously published trial, we have examined how diets rich in SFAs from either cheese or butter influence HDL-mediated CEC, compared with diets rich in either monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). Methods In a randomized crossover controlled consumption trial, 46 men and women with abdominal obesity consumed 5 isocaloric diets, each for 4 wk. Two diets were rich in SFAs either from cheese (CHEESE) or butter (BUTTER) [12.4–12.6% of energy (%E) as SFAs, 32%E as fat, 52%E as carbohydrates]. In 2 other diets, SFAs (5.8%E) were replaced with either MUFAs from refined olive oil (MUFA) or PUFAs from corn oil (PUFA). Finally, a lower fat and carbohydrate diet was used as a control (5.8%E as SFAs, 25.0%E as fat, 59%E as carbohydrates; CHO). Post-diet HDL-mediated CEC was determined ex vivo using radiolabelled J774 macrophages incubated with apolipoprotein B–depleted serum from the participants. Results Mean (±SD) age was 41.4 ± 14.2 y, and waist circumference was 107.6 ± 11.5 cm in men and 94.3 ± 12.4 cm in women. BUTTER and MUFA increased HDL-mediated CEC compared with CHEESE (+4.3%, P = 0.026 and +4.7%, P = 0.031, respectively). Exploring the significant diet × sex interaction (P = 0.044) revealed that the increase in HDL-mediated CEC after BUTTER compared with CHEESE was significant among men (+6.0%, P = 0.047) but not women (+2.9%, P = 0.19), whereas the increase after MUFA compared with CHEESE was significant among women (+9.1%, P = 0.008) but not men (–0.6%, P = 0.99). Conclusion These results provide evidence of a food matrix effect modulating the impact of dairy SFAs on HDL-mediated CEC with potential sex-related differences that deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02106208.

Cholesterol efflux capacities (CECs) are negatively associated with cardiovascular disease risk, irrespective of plasma high-density lipoprotein (HDL) cholesterol levels. Whether interventions targeting lifestyle improve HDL-CECs is unknown. Our objective was to determine whether improving dietary quality and increasing physical activity levels improves HDL-CECs in men with abdominal obesity and dyslipidemia. Our study sample included men (48 ± 8.5 yr) with an elevated waist circumference (≥90 cm) associated with dyslipidemia (triglycerides ≥1.69 and/or HDL cholesterol <1.03 mmol/l); 113 men completed a 1-yr intervention, consisting of a healthy eating and physical activity/exercise program, and 32 were included in a control group. An oral lipid tolerance test (OLTT) was performed in a subsample of 28 men who completed the intervention, and blood was collected every 2 h for 8 h. HDL-CECs were measured using [H]cholesterol-labeled J774 macrophages and HepG2 hepatocytes. The lifestyle modification program led to an overall improvement in the cardiometabolic risk profile, increases in J774-HDL-CEC by 14.1% (+0.88 ± 1.09%, P < 0.0001), HepG2-HDL-CEC by 3.4% (+0.17 ± 0.75%, P = 0.01), and HDL cholesterol and apolipoprotein A-1 levels (13.5%, P < 0.0001 and 14.9%, P < 0.0001, respectively). J774-HDL-CECs and HepG2-HDL-CECs did not change in the control group. The best predictor for changes in HDL-CEC was apolipoprotein A-1 level. The lifestyle modification program also improved HDL-CEC response in postprandial lipemia during an OLTT. HDL-CEC did not change during the OLTT. Our results suggest that increasing physical activity levels and improving diet quality can have a positive impact on both HDL quantity and quality in men with abdominal obesity and dyslipidemia.