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In a phase 2b trial involving patients with hypertriglyceridemia, the use of olezarsen (which targets APOC3 mRNA) for 6 months reduced triglyceride levels by approximately 50% as compared with placebo.

Experimental studies provided evidence about mechanisms by which cholesterol, especially high density lipoprotein cholesterol (HDL-C), could influence carcinogenesis, notably through antioxidant and anti-inflammatory properties. However, prospective studies that investigated the associations between specific lipid metabolism biomarkers and cancer risk provided inconsistent results. The objective was to investigate the prospective associations between total cholesterol (T-C), HDL-C, low density lipoprotein cholesterol, apolipoproteins A1 (apoA1) and B, and triglycerides and overall, breast and prostate cancer risk. Analyses were performed on 7,557 subjects of the Supplementation en Vitamines et Mineraux Antioxydants Study, a nationwide French cohort study. Biomarkers of lipid metabolism were measured at baseline and analyzed regarding the risk of first primary incident cancer (N = 514 cases diagnosed during follow-up, 1994-2007), using Cox proportional hazards models. T-C was inversely associated with overall (HR1(mmol/L increment) = 0.91, 95 % CI 0.82-1.00; P = 0.04) and breast (HR1mmol/L increment = 0.83, 95 % CI 0.69-0.99; P = 0.04) cancer risk. HDL-C was also inversely associated with overall (HR1mmol/L increment = 0.61, 95 % CI 0.46-0.82; P = 0.0008) and breast (HR1mmol/L increment = 0.48, 95 % CI 0.28-0.83; P = 0.009) cancer risk. Consistently, apoA1 was inversely associated with overall (HR1g/L increment = 0.56, 95 % CI 0.39-0.82; P = 0.003) and breast (HR1g/L increment = 0.36, 95 % CI 0.18-0.73; P = 0.004) cancer risk. This prospective study suggests that pre-diagnostic serum levels of T-C, HDL-C and ApoA1 are associated with decreased overall and breast cancer risk. The confirmation of a role of cholesterol components in cancer development, by further large prospective and experimental studies, may have important implications in terms of public health, since cholesterol is already crucial in cardiovascular prevention.

Abstract Background The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. Methods Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. Results Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < −0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < −0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = −0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. Conclusions The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. Trial registration NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.

Background: Corn oil (CO) and extra-virgin olive oil (EVOO) are rich sources of unsaturated fatty acids (UFA), but UFA profiles differ among oils, which may affect lipoprotein levels. Objectives: The objective of this study was to assess the effects of CO versus EVOO intake on fasting lipoprotein and subfraction cholesterol levels, apolipoprotein (apo) A1, apo B, and low-density lipoprotein particle concentrations in men and women. Subjects/Methods: As part of a weight maintenance diet, men and women were provided with food items prepared with 54 g per day of CO or EVOO (21-day treatment, 21-day washout) in a randomized, double-blind, controlled-feeding, crossover trial. Fasting lipoprotein cholesterol and related variables were determined with density gradient ultracentrifugation. Results: Among the 54 completers, CO reduced total cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apo B and LDL particle concentration to a greater extent compared with EVOO intake. Changes in LDL-C and VLDL-C contributed to the larger reduction in non-HDL-C with CO compared with EVOO intake (−0.39 mmol/l vs −0.04 mmol/l; P <0.001). The larger reduction in LDL-C by CO intake was attributable to changes ( P <0.05) caused by CO vs EVOO in large LDL 1+2 -C (−0.22 mmol/l) and intermediate-density lipoprotein cholesterol (−0.12 mmol/l). HDL-C responses did not differ between treatments, but apo A1 increased more with EVOO compared with CO intake (4.6 versus 0.7 mg/dl, respectively, P =0.016). Conclusions: CO intake reduced atherogenic lipoprotein cholesterol and particle concentrations to a larger extent than did EVOO, which may have implications for cardiovascular disease risk.

Dalcetrapib, an inhibitor of cholesteryl ester transfer protein, raises HDL cholesterol levels. In this clinical trial involving patients with an acute coronary syndrome, dalcetrapib had no beneficial effect on clinical outcomes, despite raising HDL cholesterol levels. High-density lipoproteins (HDLs) participate in the process of cellular cholesterol efflux and may have additional protective effects against atherothrombosis. 1 An inverse association between levels of HDL cholesterol and incident events of coronary heart disease has been shown in observational studies 2 , 3 and persists in most post hoc analyses and meta-analyses of trials of statin therapy for patients with cardiovascular risk factors, chronic cardiovascular disease, or recent acute coronary syndrome. 4 – 10 However, it remains uncertain whether pharmacologic intervention that raises HDL cholesterol levels results in decreased cardiovascular risk. 11 – 16 Moreover, changes in HDL cholesterol levels may not reflect changes in the . . .

The apolipoprotein E (ApoE) ε4 allele is the strongest risk factor of sporadic Alzheimer’s disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes ( APOE ε2, ε3, ε4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n  = 43 AD and n  = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE ε4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and Aβ1-42 of which the latter association was weaker and only present in APOE ε4 carriers indicating a differential involvement of ApoE in tau versus Aβ-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE ɛ4 carriers and whether this decrease in plasma ApoE predisposes A POE ɛ4 carriers to AD.

ObjectiveTo investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health.DesignA double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients.ResultsOver 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut.ConclusionThe present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota.Trial registration number NCT02099032 and NCT02146339; Results.

We examined the impact of APOE genotype on plasma lipids and glucose in a secondary analysis of data from a five-arm, randomised controlled, parallel dietary intervention trial (‘RISCK’ study), to investigate the impact of replacing saturated fatty acids (SFA) with either monounsaturated fat (MUFA) or carbohydrate of high or low glycaemic index (GI) on CVD risk factors and insulin sensitivity. We tested the impact of APOE genotype (carriage of E2 and E4 alleles versus E3/E3), determined retrospectively, on plasma lipids, lipoproteins and glucose homeostasis at baseline (n = 469), and on the change in these variables after 24 weeks of dietary intervention (n = 389). At baseline, carriers of E2 (n = 70), E4 (n = 125) and E3/E3 (n = 274) expressed marked differences in total plasma cholesterol (TC, p = 0.001), low density lipoprotein cholesterol (LDL-C, p < 0.0001), apolipoprotein B (apo B, p < 0.0001) and total to high density lipoprotein cholesterol ratio (TC:HDL-C, p = 0.002), with plasma concentrations decreasing in the order E4 > E3/E3 > E2. Following intervention, there was evidence of a significant diet x genotype interaction with significantly greater decreases in TC (p = 0.02) and apo B (p = 0.006) among carriers of E4 when SFA was replaced with low GI carbohydrate on a lower fat diet (TC −0.28 mmol/L p = 0.03; apo B −0.1 g/L p = 0.02), and a relative increase in TC (in comparison to E3/E3) when SFA was replaced with MUFA and high GI carbohydrates (TC 0.3 mmol/L, p = 0.03). Among carriers of E2 (compared with E3/E3) there was an increase in triacylglycerol (TAG) when SFA was replaced with MUFA and low GI carbohydrates 0.46 mmol/L p = 0.001). There were no significant interactions between APOE genotype and diet for changes in indices of glucose homeostasis. In conclusion, variations in APOE genotype led to differential effects on the lipid response to the replacement of SFA with MUFA and low GI carbohydrates.

Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.

Aim: To investigate the synergistic effects of exercise training and Brassica oleracea var. italica (broccoli sprout) supplementation on Apolipoprotein A-I, B-100, and J levels in men with Type 2 diabetes mellitus (T2DM). Methods: Forty-four males with T2DM were randomly assigned to four groups: Control (CG), Supplement (SG), Training (TG), and Training + Supplement (TSG) groups. Participants in the supplement groups (SG and TSG) received 10 g of broccoli supplement after meals for 12 weeks, while those in the training groups (TG and TSG) participated in a structured exercise program (resistance and aerobic), performed three times per week for 12 weeks, at intensities of 60–70% one-repetition maximum (1RM) for resistance training and 60–70% peak oxygen uptake (VO2peak) for aerobic training. Results: Circulating levels of apolipoproteins improved after 12 weeks in the TSG, TG, and SG groups. However, the TSG group exhibited the most pronounced improvements across metabolic and lipoprotein markers, reflecting an additive effect of both interventions. Specifically, the TSG group demonstrated absolute reductions in ApoB-100 (−48.30 ± 7.20 mg/dL) and ApoJ (−44.05 ± 5.76 mg/dL), along with an increase in ApoA-I (+44.92 ± 6.05 mg/dL). Main effect analysis revealed that exercise training elicited the most substantial improvements across metabolic and lipoprotein markers, with large effect sizes for glucose (η2p = 0.787), insulin (η2p = 0.640), HOMA-IR (η2p = 0.856), ApoA-I (η2p = 0.685), ApoB-100 (η2p = 0.774), ApoJ (η2p = 0.848), and HDL-C (η2p = 0.535). Supplementation showed moderate effects, particularly on HOMA-IR (η2p = 0.370), ApoA-I (η2p = 0.383), and ApoB-100 (η2p = 0.334), supporting an additive but exercise-dominant benefit. The combined intervention group (TSG) showed the most pronounced improvements across all measured outcomes, with large effect sizes for ApoA-I (η2p = 0.883), glucose (η2p = 0.946), insulin (η2p = 0.881), HOMA-IR (η2p = 0.904), and ApoJ (η2p = 0.852). Conclusions: The effects of combining training and broccoli sprout supplementation on apolipoprotein levels are likely to result from the activation of two separate pathways, one from training and the other from supplementation. This dual-modality intervention could serve as an effective complementary strategy in managing metabolic and cardiovascular risk factors for individuals with T2DM. However, the magnitude of change induced by the combination of exercise training and broccoli supplementation was largely driven by the training component, with supplementation providing complementary but less consistent benefits.