Functionality of postprandial larger HDL2 particles is enhanced following CETP inhibition therapy

Bellanger, Natacha; Julia, Zélie; Villard, Elise F.; Khoury, Petra El; Duchêne, Emilie; Chapman, M. John; Fournier, Natalie; Goff, Wilfried Le; Guérin, Maryse

doi:10.1016/j.atherosclerosis.2011.12.027

Cited by 31 publications

(19 citation statements)

References 35 publications

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“…210 In agreement with these observations, in male subjects with high-risk HDL-cholesterol levels (<40 mg/dl), 6-week combination treatment with torcetrapib (60 mg/day) and atorvastatin (10 mg/day) enhanced the capacity of large HDL2 particles to mediate cholesterol efflux via SR-BI and the delivery of HDL cholesteryl esters to hepatoma cells when compared to atorvastatin monotherapy. 211 Similar findings were reported from a study in patients with mixed hyperlipidemia where HDL2-mediated cholesterol efflux and uptake of HDL cholesteryl esters by hepatocytes were shown to be augmented by a 6-week period of combined torcetrapib/atorvastatin (60/10 mg/day) therapy. 212 The treatment of hamsters with torcetrapib increased the mobilization of radiolabeled cholesterol from peritoneal macrophages into plasma HDL and subsequent excretion into stool.…”

Section: Fibratessupporting

confidence: 83%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Fibratessupporting

confidence: 83%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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“…The increases in HDL2b result in an increase of non-ABCA1-mediated cholesterol efflux and, thus, influence total efflux. 39 Indeed, this is what has been observed with the different agents ranging from an increase in total efflux by ≈9% with dalcetrapib to a 2.4-fold increase with anacetrapib. 40,41 CETPis should also inhibit homotypic transfer of cholesterol esters between HDL subclasses resulting in an increase in lipid-poor pre-β HDL.…”

Section: On-target Effectssupporting

confidence: 65%

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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“…In such patients, postprandial phase is associated with an increase in cholesterol efflux from macrophages as a result of CETP-mediated intravascular HDL remodeling and liberation of lipid poor/lipid free apolipoprotein (apo) AI. 16 However, enhanced CETP-mediated CE transfer from HDL to postprandial TRL induces formation and accumulation of CE-enriched lipoprotein remnants that represent preferential precursors of atherogenic small dense LDL particles, displaying a reduced affinity for the hepatic lowdensity lipoprotein receptor. 17 Equally, HDL particles generated during postprandial phase have been shown to display a reduced ability to deliver CE to the liver.…”

Section: Conclusion-ern/lrptmentioning

confidence: 99%

“…17 Equally, HDL particles generated during postprandial phase have been shown to display a reduced ability to deliver CE to the liver. 16 Taken together, these observations indicate that despite improvement of cholesterol efflux from macrophage, postprandial lipemia is associated with a global reduction of RCT efficacy because the ultimate return of cholesterol to the liver, directly or indirectly, is reduced in patients displaying a low HDL-C phenotype. Niacin has long been known to efficiently reduce the coexisting lipid triad consisting of TRL, TRL remnants, and small dense LDL particles in hyperlipidemic patients.…”

mentioning

confidence: 92%

Extended-Release Niacin/Laropiprant Improves Overall Efficacy of Postprandial Reverse Cholesterol Transport

Khoury

Waldmann

Huby

et al. 2016

ATVB

Self Cite

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Objectives-Postprandial atherogenic lipoproteins, characterizing high-risk patients, correlate positively with cardiovascular events. Although the effect of niacin on fasting lipids is well established, its impact on atheroprotective reverse cholesterol transport (RCT) pathway and on functional features of circulating lipoproteins during the postprandial state remains indeterminate. Approach and Results-We evaluated RCT pathway during postprandial phase in dyslipidemic patients displaying a low high-density lipoprotein (HDL) cholesterol phenotype. Ten subjects on stable statin therapy received 1 g/20 mg extendedrelease niacin/laropiprant (ERN/LRPT) for 4 weeks followed by 2 g/40 mg ERN/LRPT for additional 8 weeks. At each experimental period, postprandial hypertriglyceridemia and major steps of RCT, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein-mediated cholesteryl ester transfer, and hepatic HDL-cholesteryl ester selective uptake were evaluated. Equally, the capacity of postprandial HDL particles isolated from patients before and after ERN/LRPT treatment to mediate RCT to feces was evaluated in vivo in human apolipoprotein B/cholesteryl ester transfer protein double transgenic mouse model. Compared with baseline, ERN/LRPT significantly reduced postprandial hypertriglyceridemia (incremental area under the curve-triglyceride: −53%; P=0.02). Postprandial increase in endogenous plasma cholesteryl ester transfer protein activity was completely abolished after ERN/LRPT treatment. Despite a slight reduction in plasma cholesterol efflux capacity from human THP-1 macrophages, evaluation of global RCT efficacy by combining both ex vivo and in vivo approaches indicate that postprandial HDL particles formed under ERN/LRPT therapy displayed a greater capacity for HDL-mediated RCT to feces. 9 It has been demonstrated that the capacity of HDL to mediate cholesterol efflux represents a strong predictor of the presence and the extend of atherosclerosis. Conclusions-ERN/LRPT10 Equally, an inverse association between the prevalence of coronary disease and HDL efflux capacity has been observed; however, HDL-mediated efflux was paradoxically associated with increase in prospective risk of myocardial infarction, stroke, and death.11 These observations suggest that it is important to consider the overall efficacy of RCT pathway, including not only macrophage cholesterol efflux, but also the return of cholesterol to the liver and the ultimate excretion of cholesterol from the body.The efficacy of RCT pathway can be influenced by several factors. Postprandial lipemia, characterized by a transient production and accumulation of TRL, is associated with an acceleration of RCT.12,13 Indeed, it is important to consider that intravascular metabolism of both TRL and HDL is intimately intricate: (1) CETP-mediated neutral lipid heteroexchange between TRL and HDL induces the formation of cholesteryl ester (CE)-rich TRL remnants and TG-rich HDL particles and (2) the transfer of phospholipids and cholester...

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Functionality of postprandial larger HDL2 particles is enhanced following CETP inhibition therapy

Cited by 31 publications

References 35 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

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

Extended-Release Niacin/Laropiprant Improves Overall Efficacy of Postprandial Reverse Cholesterol Transport

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