Dataset Information

Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level.

ABSTRACT:

Objective

The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD.

Methods

HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum.

Results

While cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001).

Conclusion

Our results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed.

SUBMITTER: Paavola T

PROVIDER: S-EPMC5313225 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level.

Paavola Timo T Kuusisto Sanna S Jauhiainen Matti M Kakko Sakari S Kangas-Kontio Tiia T Metso Jari J Soininen Pasi P Ala-Korpela Mika M Bloigu Risto R Hannuksela Minna L ML Savolainen Markku J MJ Salonurmi Tuire T

PloS one 20170216 2

<h4>Objective</h4>The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD.<h4>Methods</h4>HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macropha ...[more]

PMID: 28207870

Similar Datasets

Project description:BackgroundAlthough HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity-a prototypical measure of HDL function-has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain.MethodsWe measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40-79 years, assessed in 1993-97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants.FindingsCholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=-0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51-0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70-0·90) for a per-SD change in cholesterol efflux capacity.InterpretationHDL cholesterol efflux capacity might provide an alternative mechanism for therapeutic modulation of the HDL pathway beyond HDL cholesterol concentration to help reduce risk of coronary heart disease.FundingUS National Institutes of Health, UK Medical Research Council, Cancer Research UK.

Project description:It is unclear whether high-density lipoprotein (HDL) cholesterol concentration plays a causal role in atherosclerosis. A more important factor may be HDL cholesterol efflux capacity, the ability of HDL to accept cholesterol from macrophages, which is a key step in reverse cholesterol transport. We investigated the epidemiology of cholesterol efflux capacity and its association with incident atherosclerotic cardiovascular disease outcomes in a large, multiethnic population cohort.We measured HDL cholesterol level, HDL particle concentration, and cholesterol efflux capacity at baseline in 2924 adults free from cardiovascular disease who were participants in the Dallas Heart Study, a probability-based population sample. The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascular causes. The median follow-up period was 9.4 years.In contrast to HDL cholesterol level, which was associated with multiple traditional risk factors and metabolic variables, cholesterol efflux capacity had minimal association with these factors. Baseline HDL cholesterol level was not associated with cardiovascular events in an adjusted analysis (hazard ratio, 1.08; 95% confidence interval [CI], 0.59 to 1.99). In a fully adjusted model that included traditional risk factors, HDL cholesterol level, and HDL particle concentration, there was a 67% reduction in cardiovascular risk in the highest quartile of cholesterol efflux capacity versus the lowest quartile (hazard ratio, 0.33; 95% CI, 0.19 to 0.55). Adding cholesterol efflux capacity to traditional risk factors was associated with improvement in discrimination and reclassification indexes.Cholesterol efflux capacity, a new biomarker that characterizes a key step in reverse cholesterol transport, was inversely associated with the incidence of cardiovascular events in a population-based cohort. (Funded by the Donald W. Reynolds Foundation and others.).

Project description:Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preβ-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preβ-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) preβ-1 concentrations than controls, but the functionality of their preβ-1 particles (preβ-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either preβ-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preβ-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.

Project description:BackgroundProper functioning of high-density lipoprotein (HDL) is necessary for protection against sepsis. However, previous work has demonstrated that HDL becomes oxidized and dysfunctional (Dys-HDL) during sepsis. Older (aged >65 years) patients are at particularly high risk of sepsis and poor outcomes from sepsis.Study objectiveThe aim of the study was to compare functional properties of HDL (cholesterol efflux capacity and paraoxonase enzyme 1 [PON-1] activity) and Dys-HDL between older (aged >65 years) sepsis patients and older healthy volunteers.MethodsThis was a subanalysis of a prospective study in which patients with sepsis were prospectively enrolled from the emergency department within the first 24 h. Serum and plasma samples were drawn from septic patients and age- and sex-matched control subjects. Percent cholesterol efflux, HDL inflammatory index, and PON1 activity were measured. Data were analyzed using Student t test or Wilcoxon rank-sum test.ResultsTen sepsis and 10 healthy controls were analyzed. Mean age of sepsis patients (80 ± 2 years [SD]) and control subjects (77 ± 2 years) was similar (P = 0.31). Mean systolic blood pressures were significantly different in sepsis patients (113 ± 8 mmHg) compared with controls (133 ± 6 mmHg) (P = 0.049). Median SOFA scores for sepsis patients were 5.5 (interquartile range [IQR] 4-9). Mean percent cholesterol efflux was significantly reduced in sepsis (24.1 ± 1.2%) compared with controls (31.5 ± 1.0%) (P < 0.001). HDL inflammatory index was also significantly elevated in septic patients (1.63, IQR 1.3-2.34) compared with controls (0.62, IQR 0.56-0.67) (P < 0.001). However, PON1 activity was not significantly different between septic patients (70.3 ± 16.3 nmol/min/mL) and control subjects (88.8 ± 18.3 nmol/min/mL).ConclusionsCholesterol efflux capacity seems to be significantly impaired in sepsis patients who also exhibited a higher index of Dys-HDL. The findings suggest that HDL function may be impaired in older individuals with sepsis.

Dataset Information

Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level.

Objective

Methods

Results

Conclusion

Publications

Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets