555 research outputs found
Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease?
No full textApoC-III was discovered almost 50 years ago, but for many years, it did not attract much attention. However, as epidemiological and Mendelian randomization studies have associated apoC-III with low levels of triglycerides and decreased incidence of cardiovascular disease (CVD), it has emerged as a novel and potentially powerful therapeutic approach to managing dyslipidemia and CVD risk. The atherogenicity of apoC-III has been attributed to both direct lipoprotein lipase-mediated mechanisms and indirect mechanisms, such as promoting secretion of triglyceride-rich lipoproteins (TRLs), provoking proinflammatory responses in vascular cells and impairing LPL-independent hepatic clearance of TRL remnants. Encouraging results from clinical trials using antisense oligonucleotide, which selectively inhibits apoC-III, indicate that modulating apoC-III may be a potent therapeutic approach to managing dyslipidemia and cardiovascular disease risk.Peer reviewe
Metabolism of Triglyceride-Rich Lipoproteins
No full textTriglycerides are critical lipids as they provide an energy source that is both compact and efficient. Due to its hydrophobic nature triglyceride molecules can pack together densely and so be stored in adipose tissue. To be transported in the aqueous medium of plasma, triglycerides have to be incorporated into lipoprotein particles along with other components such as cholesterol, phospholipid and associated structural and regulatory apolipoproteins. Here we discuss the physiology of normal triglyceride metabolism, and how impaired metabolism induces hypertriglyceridemia and its pathogenic consequences including atherosclerosis. We also discuss established and novel therapies to reduce triglyceride-rich lipoproteins.Peer reviewe
Dietary omega-3 polyunsaturated fatty acid intake is related to a protective high-density lipoprotein subspecies profile independent of genetic effects: A monozygotic twin pair study
No full textBackground: Studies on diet and high-density lipoprotein (HDL) subspecies distribution are limited. Objective: We examined the relationship between macronutrient composition and lipoprotein particle size and HDL subspecies independent of genetic effects by studying monozygotic (MZ) twins. Methods: 24 healthy MZ twin pairs aged 23-33 years were identified from two longitudinal population-based studies, FinnTwin16 and FinnTwin12. Total energy and nutrient intake were assessed with 3-day food records and physical activity was measured by the Baecke index. HDL subspecies distribution was determined by non-denaturing gradient gel electrophoresis. Associations between diet composition and HDL mean particle size were determined by multivariate nutrient density models adjusted for confounding variables. Results: Substituting one energy percentage from omega-3 polyunsaturated fatty acids (n-3 PUFAs) for a corresponding amount of energy from other type of fats was related to changes in the relative proportions of the HDL subspecies 2b, 3a and 3b toward a larger mean particle size in men (beta +/- SE: 1.00 +/- 0.26 nm, p = 0.004) and women (beta +/- SE: 0.90 +/- 0.21 nm, p = 0.001). This association remained significant in analyses controlling for genetic and shared environmental influences using within-pair differences of the measures in MZ twin pairs (beta +/- SE: 0.37 +/- 0.14 nm, p = 0.019). Twins with the higher n-3 PUFA intake had significantly higher proportions of large HDL2b particles and lower proportions of smaller-sized HDL3a and HDL3b particles as compared to their co-twins with lower intakes (p < 0.05). Conclusions: Our data suggest that n-3 PUFA intake is associated with a favorable change in the distribution of HDL subspecies towards larger particles independent of genetic and shared environmental factors. (C) 2011 Elsevier Ireland Ltd. All rights reserved
Macrophage cholesterol efflux to plasma and HDL in subjects with low and high homocysteine levels: A FIELD substudy
No full textObjectives: Increases of homocysteine (Hcy) by fenofibrate correlated inversely to changes in HDL-C and apoA-I in the FIELD study. This finding raised the question whether high Hcy may influence HDL function and counteract benefits of fenofibrate on cardiovascular outcomes. In a subset of the FIELD study we investigated whether fenofibrate therapy or high Hcy, separately or in concert, modulate: (1) ability of plasma or HDL to facilitate cholesterol efflux from THP-1 foam cells; (2) plasma potential to generate pre beta-HDL; (3) plasma phospholipid transfer protein (PLTP) activity, serum PON-1 mass and activity, HDL particle size and distribution. Methods: We selected 33 subjects in the FIELD fenofibrate arm according to quartiles of Hcy at 5th year: 17 subjects were in the lowest (Low Hcy group) and 16 subjects were in the highest quartile (High Hcy group). In addition, 14 subjects allocated to placebo were matched by close-out Hcy levels to Low Hcy group. This design allowed us to examine the effects of both fenofibrate (comparison between placebo vs Low Hcy groups) and Hcy (comparison between close-out Low and High Hcy groups) on plasma and HDL ability to facilitate cellular cholesterol removal in the efflux assay in vitro using THP-1 foam cells. Results: Hcy levels were 13.3 +/- 0.7 mu mol/L (placebo), 13.2 +/- 2 mu mol/L (Low Hcy) and 27.4 +/- 6.5 mu mol/L (High Hcy). Cholesterol efflux values to HDL and plasma, percentage of plasma pre beta-HDL, PLTP activity, serum PON-1 mass and HDL particle size and distribution were similar in both fenofibrate groups and comparable to those of the placebo group. Conclusions: In the present study cohort fenofibrate and high Hcy levels did not modulate HDL and plasma functions in the first step of reverse cholesterol transport, cholesterol efflux from foam cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved
Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans
No full textTo develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia.Peer reviewe
Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study
No full textAIMS: The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99–3.36] and 1.37 [95% CI: 1.27–1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58–1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26–1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk.
CONCLUSION: Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL
Biosynthesis and metabolism of ApoB-containing lipoproteins
No full textRecent advances in human genetics, together with a substantial body of epidemiological, preclinical and clinical trial evidence, strongly support a causal relationship between triglyceride-rich lipoproteins (TRLs) and atherosclerotic cardiovascular disease. Consequently, the secretion and metabolism of TRLs have a significant impact on cardiovascular health. This knowledge underscores the importance of understanding the molecular mechanisms and regulation of very-low-density lipoprotein (VLDL) and chylomicron biogenesis. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL, leading to many ground-breaking molecular insights. Furthermore, the identification of molecular control mechanisms related to triglyceride metabolism has greatly advanced our understanding of the complex metabolism of TRLs. In this review, we explore recent advances in the assembly, secretion, and metabolism of TRLs. We also discuss available treatment strategies for hypertriglyceridemia
Improved Estimation of Human Lipoprotein Kinetics with Mixed Effects Models
No full textContext Mathematical models may help the analysis of biological systems by providing estimates of otherwise un-measurable quantities such as concentrations and fluxes. The variability in such systems makes it difficult to translate individual characteristics to group behavior. Mixed effects models offer a tool to simultaneously assess individual and population behavior from experimental data. Lipoproteins and plasma lipids are key mediators for cardiovascular disease in metabolic disorders such as diabetes mellitus type 2. By the use of mathematical models and tracer experiments fluxes and production rates of lipoproteins may be estimated. Results We developed a mixed effects model to study lipoprotein kinetics in a data set of 15 healthy individuals and 15 patients with type 2 diabetes. We compare the traditional and the mixed effects approach in terms of group estimates at various sample and data set sizes. Conclusion We conclude that the mixed effects approach provided better estimates using the full data set as well as with both sparse and truncated data sets. Sample size estimates showed that to compare lipoprotein secretion the mixed effects approach needed almost half the sample size as the traditional method.Peer reviewe
Not enough known about fenofibrate's kidney effects in people with Type 2 diabetes
No full textGlobally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data.Peer reviewe
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