Elevated CETP Activity Improves Plasma Cholesterol Efflux Capacity From Human Macrophages in Women

Villard, Elise F.; Khoury, Petra El; Duchêne, Emilie; Bonnefont‐Rousselot, Dominique; Clément, Karine; Bruckert, Éric; Bittar, Randa; Goff, Wilfried Le; Guérin, Maryse

doi:10.1161/atvbaha.112.252841

Cited by 35 publications

(25 citation statements)

References 62 publications

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“…Schierer and cols. (61), similar to other authors (58,59), proposed that low CETP is associated with higher cardiovascular risk.…”

Section: Cetp and Its Lipoprotein Subclassessupporting

confidence: 80%

“…However, their use as a risk biomarker is still controversial. Some researchers (58,59) observed, in high risk individuals, associations of CETP with cholesterol efflux capacity, which is in agreement with the protective role of the enzyme in atherosclerosis. In a longitudinal study with 6,780 individuals, variation in the concentrations of CETP did not affect the importance of the effect of apo B/apo A-I and CT/HDL-C ratios for the occurrence in the first cardiovascular event (60).…”

Section: Cetp and Its Lipoprotein Subclassessupporting

confidence: 63%

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Reassessing lipid metabolism and its potentialities in the prediction of cardiovascular risk

Silva

Almeida-Pititto

Ferreira

2015

Arch. Endocrinol. Metab.

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There are numerous particles, enzymes, and mechanisms in the lipid metabolism that are involved in the genesis of cardiovascular disease (CVD). Given its prevalence in populations and its impact on mortality, it is relevant to review the lipid metabolism as it may potentially provide subsidies to better prediction. This article reviews the importance of traditional cardiovascular risk factors and comments on the potential of novel lipid biomarkers involved in the physiopathology of CVD. The Framingham cohorts proved the role of traditional risk factors (physical inactivity, smoking, blood pressure, total cholesterol, LDL-C, HDL-C, plasma glucose) in the prediction of cardiovascular events. However, a significant number of individuals that suffer from a cardiovascular event has few or none of these factors. Such finding indicates the need for new biomarkers able to identify plaques that are more susceptible to rupture. Some of bloodstream biomarkers related to lipid metabolism are modified LDL particles, apolipoprotein AI (apo AI), apolipoprotein B, lipoprotein (a) [Lp (a)], cholesteryl ester transfer protein (CETP), subtypes of LDL and HDL particles, and lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ). These factors participate in the atherosclerotic process, and are abnormal in individuals at high risk, or in those who suffered from a cardiovascular event. Lp (a) determination is already employed in clinical practice and should be included as a reference parameter for CVD monitoring. Furthermore, there are expectations for wider use of apo B, non-HDL cholesterol and total cholesterol / HDL-C determination to improve cardiovascular risk assessment. Arch Endocrinol Metab. 2015;59(2):171-80

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“…Schierer and cols. (61), similar to other authors (58,59), proposed that low CETP is associated with higher cardiovascular risk.…”

Section: Cetp and Its Lipoprotein Subclassessupporting

confidence: 80%

Section: Cetp and Its Lipoprotein Subclassessupporting

confidence: 63%

Reassessing lipid metabolism and its potentialities in the prediction of cardiovascular risk

Silva

Almeida-Pititto

Ferreira

2015

Arch. Endocrinol. Metab.

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“…8 This was further substantiated by more recent studies showing that endogenous CETP activity was positively associated with plasma capacity to mediate free cholesterol efflux from human macrophages. 9 Similar results were shown in the Ludwigshafen Risk and Cardiovascular Health Study, where HDL efflux capacity was measured in 154 patients, who were selected based on either low (n=77) or high CETP concentration (n=77). Low plasma concentrations of CETP were associated with impaired HDL function, suggesting an atheroprotective role of CETP, at least in patients at high risk for coronary artery disease (CAD).…”

Section: Circulationsupporting

confidence: 62%

Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk?

2015

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T he notion that cardiovascular disease (CVD) remains a major burden to global morbidity and mortality has driven the quest for novel pharmaceutical agents to further reduce CVD risk. In this respect, cholesteryl ester transfer protein (CETP) has gained considerable interest, ever since one of the first descriptions in the 1980s that low CETP levels attributed to deleterious mutations in CETP were associated with longevity, 1 a finding that was later suggested to result from higher high-density lipoprotein (HDL) cholesterol (-C) levels.2 The role of HDL as a causal determinant in CVD risk, however, has not been established, and HDL-C levels might very well be a risk marker rather than a risk factor. 3,4 Response by Barter et al on p 440It is striking that 2 decades after the first description of the potential beneficial effects of CETP mutations, the effect of CETP on CVD risk remains inconclusive, and this, by itself, suggests that CETP may not be an attractive therapeutic target for the prevention of CVD. The hypothesis that CETP inhibition would result in CVD risk reduction has been questioned in the past. Fielding and Havel, 5 leading scientists in HDL metabolism, suggested that the increase in HDL-C induced by CETP inhibition could be misleading and in fact not be associated with CVD risk reduction. HDL particles formed on CETP inhibition are cholesteryl ester enriched and may lose their antiatherogenic bioactivity. Apart from insights from HDL metabolism, data derived from animal studies, large prospective human population studies, and clinical trials have generated conflicting results with respect to the role of CETP in CVD risk.We set out to summarize the published data that cast doubt on CETP as a therapeutic target to lower CVD risk. We focus on data derived from animal and human studies and we emphasize that the data presented are focused on the negative arguments, and these should be balanced against the arguments in favor of CETP inhibition described by Barter et al in this edition of Circulation. 6 CETP PhysiologyCETP, secreted by the liver, macrophages, and adipose tissue, plays a pivotal role in the transfer of cholesteryl esters from HDL to proatherogenic very low-density lipoprotein and lowdensity lipoprotein (LDL) particles in exchange for triglycerides (TGs). 7 The TG content in HDL particles is subsequently hydrolyzed by hepatic lipase. The transfer induced by CETP results in an increase of cholesterol within the LDL fraction and a decrease within HDL particles, especially in patients with elevated TG levels.

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“…Effl ux assays were performed using human THP-1 macrophages and several cellular models, Fu5AH, CHO-K1, CHOhABCG1, and CHO-hABCA1, as previously described ( 27 ). 3H-cholesterol-labeled cells were incubated for 4 h at 37°C in the presence of 40-fold diluted total plasma or individual HDL subfractions [15 g phospholipid/ml for cholesterol loaded-THP-1 macrophages; 10 g phospholipid/ml for Fu5AH (SR-BI-dependent effl ux); 5 g phospholipid/ml for CHO-K1 and CHO-hABCG1; is a lipid-infl ammatory-oxidative disease.…”

Section: Fc Effl Ux Assaysmentioning

confidence: 99%

“…Plasma effl ux capacity was expressed as a relative effl ux obtained by dividing the fractional effl ux of sample values by those obtained with the standard plasma. The capacity of individual HDL subfractions to mediate FC efflux is expressed as the percentage of cholesterol effl ux per mole of acceptor particle, as previously described ( 27 ). All effl ux experiments were performed in triplicate for each sample.…”

Section: Fc Effl Ux Assaysmentioning

confidence: 99%

Plasma cholesterol efflux capacity from human THP-1 macrophages is reduced in HIV-infected patients: impact of HAART

Khoury

Ghislain

Villard

et al. 2015

Journal of Lipid Research

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Coronary heart disease rates are expected to be higher as the human immunodefi ciency virus (HIV) population ages. Controversy still exists as to whether HIV infection per se or its treatment increases the rate of coronary heart disease. Highly active antiretroviral therapy (HAART) has been associated with the occurrence of cardiovascular events in HIV-infected patients ( 1, 2 ). However, in the Strategies for Managment of Antiretroviral Therapy (SMART) trial, the episodic use of HAART was associated with an increased risk of CVD when compared with continuous HAART use ( 3 ). It is now well-established that atherosclerosis Abstract The capacity of HDL to remove cholesterol from macrophages is inversely associated with the severity of angiographic coronary artery disease . The effect of human immunodefi ciency virus (HIV) infection or its treatment on the ability of HDL particles to stimulate cholesterol effl ux from human macrophages has never been studied. We evaluated the capacity of whole plasma and isolated HDL particles from HIV-infected subjects (n = 231) and uninfected controls (n = 200), as well as in a subset of 41 HIV subjects receiving highly active antiretroviral therapy (HAART) to mediate cholesterol effl ux from human macrophages. Plasma cholesterol effl ux capacity was reduced ( ؊ 12%; P = 0.001) in HIV patients as compared with controls. HIV infection reduced by 27% ( P < 0.05) the capacity of HDL subfractions to promote cholesterol effl ux from macrophages. We observed a reduced ABCA1-dependent effl ux capacity of plasma ( ؊ 27%; P < 0.0001) from HIV-infected subjects as a result of a reduction in the effl ux capacity of HDL3 particles. HAART administration restored the capacity of plasma from HIV patients to stimulate cholesterol effl ux from human macrophages (9.4%; P = 0.04). During HIV infection, the capacity of whole plasma to remove cholesterol from macrophages is reduced, thus potentially contributing to the increased coronary heart disease in the HIV population. HAART administration restored the removal of cholesterol from macrophages by increasing HDL functionality. -El Khoury, P., M. Ghislain,

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Elevated CETP Activity Improves Plasma Cholesterol Efflux Capacity From Human Macrophages in Women

Cited by 35 publications

References 62 publications

Reassessing lipid metabolism and its potentialities in the prediction of cardiovascular risk

Reassessing lipid metabolism and its potentialities in the prediction of cardiovascular risk

Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk?

Plasma cholesterol efflux capacity from human THP-1 macrophages is reduced in HIV-infected patients: impact of HAART

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