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Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size.

ABSTRACT: Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given.

SUBMITTER: van Schalkwijk DB

PROVIDER: S-EPMC2781312 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size.

van Schalkwijk Daniël B DB de Graaf Albert A AA van Ommen Ben B van Bochove Kees K Rensen Patrick C N PC Havekes Louis M LM van de Pas Niek C A NC Hoefsloot Huub C J HC van der Greef Jan J Freidig Andreas P AP

Journal of lipid research 20090610 12

Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease r ...[more]

PMID: 19515990

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Project description:BackgroundProspective cohort studies have found a relation between sugar-sweetened beverage consumption (SSB; sodas and fruit drinks) and dyslipidemia. There is limited evidence linking SSB consumption to emerging features of dyslipidemia, which can be characterized by variation in lipoprotein particle size, remnant-like particle (RLP), and apolipoprotein concentrations.ObjectiveTo examine the association between SSB consumption and plasma lipoprotein cholesterol, apolipoprotein, and lipoprotein particle size concentrations among US adults.MethodsWe examined participants from the Framingham Offspring Study (FOS) (1987-1995; n = 3047) and the Women's Health Study (1992; n = 26,218). Plasma LDL-C, apolipoprotein (apo) B, HDL-C, apoA1, triglyceride (TG), non-HDL-C, total: HDL-cholesterol ratio, and apoB: apoA1 concentrations were quantified in both cohorts, and apoE, apoC3, RLP-TG, and RLP-cholesterol concentrations in FOS only. Lipoprotein particle sizes were calculated from NMR signals for lipoprotein particle subclass concentrations (triglyceride-rich lipoprotein particles [TRL-P; very large, large, medium, small, and very small], LDL-particles [LDL-P; large, medium, and small], HDL-particles [HDL-P; large, medium, and small]). SSB consumption was estimated from food frequency questionnaire data. We examined the associations between SSB consumption and all lipoprotein and apoprotein measures in linear regression models, adjusting for confounding factors, such as lifestyle, diet, and traditional lipoprotein risk factors.ResultsSSB consumption was positively associated with LDL-C, apoB, TG, RLP-TG, RLP-C, non-HDL-C concentrations and total: HDL cholesterol and apoB: apoA1 ratio, and negatively associated with HDL-C and apoA1 concentrations (P-trend ranges from < 0.0001 to 0.003). After adjustment for traditional lipoprotein risk factors, SSB consumers had smaller LDL-P and HDL-P sizes, lower concentrations of large LDL-P and medium HDL-P, and higher concentrations of small LDL-P, small HDL-P, and large TRL-P (P-trend ranges from < 0.0001 to 0.0009).ConclusionsHigher SSB consumption was associated with multiple emerging features of dyslipidemia that have been linked to higher cardiometabolic risk in US adults.

Project description:BackgroundChemically measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL measures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy.Methods and resultsIn Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL-C and apolipoprotein A-I (apoA-I) were chemically assayed in 10 886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/d or placebo. Levels were examined with first CVD (n=234). HDL-P correlated better with apoA-I (Spearman r=0.69, P<0.0001) than with HDL-C (r=0.55, P<0.0001). Rosuvastatin lowered low-density lipoprotein cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%), and HDL size (1.2%); all P<0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% confidence interval per 1 standard deviation: 0.79 [0.63-0.98], 0.75 [0.62-0.92], and 0.81 [0.67-0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57-0.93, P=0.01) than HDL-C (0.82, 0.63-1.08, P=0.16) or apoA-I (0.86, 0.67-1.10, P=0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53-0.97, P=0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD.ConclusionsIn the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than chemically measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT00239681.

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Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size.

Publications

Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size.

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