Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

Boekholdt, S. Matthijs; Kuivenhoven, J.A.; Wareham, Nicholas J.; Peters, Ron J.G.; Jukema, J. Wouter; Luben, Robert; Bingham, Sheila; Day, Nicholas E.; Kastelein, John J.P.; Khaw, Kay‐Tee

doi:10.1161/01.cir.0000141730.65972.95

Cited by 198 publications

(35 citation statements)

References 44 publications

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“…Most interestingly, previous studies (11)(12)(13) in human populations are consistent with the association of high CETP with an increase in coronary heart disease, in particular in subjects with elevated triglycerides.…”

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confidence: 78%

Molecular Mechanism of the Blockade of Plasma Cholesteryl Ester Transfer Protein by Its Physiological Inhibitor Apolipoprotein CI

Dumont

Gautier

Barros

et al. 2005

Journal of Biological Chemistry

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Genetically engineered mice demonstrated that apolipoprotein (apo) CI is a potent, physiological inhibitor of plasma cholesteryl ester transfer protein (CETP) activity. The goal of this study was to determine the molecular mechanism of the apoCI-mediated blockade of CETP activity. Kinetic analyses revealed that the inhibitory property of apoCI is independent of the amount of active CETP, but it is tightly dependent on the amount of high density lipoproteins (HDL) in the incubation mixtures. The electrostatic charge of HDL, i.e. the main carrier of apoCI in human plasma, is gradually modified with increasing amounts of apoCI, and the neutralization of apoCI lysine residues by acetylation produces a marked reduction in its inhibitory potential. The inhibitory property of full-length apoCI is shared by its C-terminal ␣-helix with significant electrostratic properties, whereas its N-terminal ␣-helix with no CETP inhibitory property has no effect on HDL electronegativity. Finally, binding experiments demonstrated that apoCI and to a lower extent its C-terminal ␣-helix are able to disrupt CETP-lipoprotein complexes in a concentration-dependent manner. It was concluded that the inhibition of CETP activity by apoCI is in direct link with its specific electrostatic properties, and the apoCI-mediated reduction in the binding properties of lipoproteins results in weaker CETP-HDL interactions and fewer cholesteryl ester transfers.The cholesteryl ester transfer protein (CETP) 4 mediates the exchange of neutral lipids, i.e. cholesteryl esters and triglycerides between plasma lipoproteins (1, 2). Through its action, CETP can influence the atherogenicity of the lipoprotein profile (2-4), and recent studies (5-7) support a potential interest in inhibiting CETP activity in vivo by means of either anti-CETP immunotherapy, antisense oligonucleotides, or specific pharmacological inhibitors. In particular, the latest pharmacological interventions with small anti-CETP molecules in human populations demonstrated that CETP inhibition markedly increases HDL cholesterol levels and also decreases low density lipoprotein (LDL) cholesterol levels (8 -10). Most interestingly, previous studies (11-13) in human populations are consistent with the association of high CETP with an increase in coronary heart disease, in particular in subjects with elevated triglycerides.Besides interventional studies with exogenous compounds, a number of studies (14 -19) indicated that plasma CETP activity can be modulated by endogenous factors, among them the apolipoprotein components of circulating lipoproteins. Recently, apolipoprotein CI, i.e. a 6.6-kDa HDL apolipoprotein, was identified as a potent CETP inhibitor (20). In contrast to other putative apolipoprotein candidates that were identified only through in vitro experiments, the ability of apoCI to decrease specific CETP activity was documented in vivo through studies in CETPTg/apoCI-KO and CETPTg/HuapoCITg (transgenic mouse to both human CETP and human apolipoprotein CI) mice (21, 22). Although it was ...

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supporting

confidence: 78%

Molecular Mechanism of the Blockade of Plasma Cholesteryl Ester Transfer Protein by Its Physiological Inhibitor Apolipoprotein CI

Dumont

Gautier

Barros

et al. 2005

Journal of Biological Chemistry

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“…In human plasma, CETP plays a potentially proatherogenic role by moving CE from HDL to very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles, thereby lowering atheroprotective HDLc and raising proatherogenic VLDLc and LDLc. Apparently, the risk of CAD is proportional to the plasma levels of CETP [5]. In fact, It is quite common within the CAD population to have elevated CETP plasma protein levels that are 2-to 3-fold higher than concentrations typically found in the plasma of normal subjects (1-3 mg/mL) [6].…”

Section: Introductionmentioning

confidence: 99%

Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration

Khalaf

Sheikha

Bustanji

et al. 2010

European Journal of Medicinal Chemistry

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“…27 The study had a nested case-control design, including 1138 patients who were apparently healthy at baseline but developed CAD during follow-up, and 2237 matched control subjects, who remained free of any CVD. overall, CETP levels did not differ significantly between patients and control subjects (4.0±2.2 versus 3.8±2.1 mg/L; P=0.07).…”

Section: Population Studies Of Cetp Mass and Activitymentioning

confidence: 99%

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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Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

Cited by 198 publications

References 44 publications

Molecular Mechanism of the Blockade of Plasma Cholesteryl Ester Transfer Protein by Its Physiological Inhibitor Apolipoprotein CI

Molecular Mechanism of the Blockade of Plasma Cholesteryl Ester Transfer Protein by Its Physiological Inhibitor Apolipoprotein CI

Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration

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

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