Differential Interaction of the Human Cholesteryl Ester Transfer Protein with Plasma High Density Lipoproteins (HDLs) from Humans, Control Mice, and Transgenic Mice to Human HDL Apolipoproteins

Masson, David; Duverger, Nicolas; Emmanuel, Florence; Lagrost, Laurent

doi:10.1074/jbc.272.39.24287

Cited by 13 publications

(15 citation statements)

References 49 publications

(30 reference statements)

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“…Indeed, recent in vitro analysis of the inhibition of CETP activity by HDL from wild-type mice and apoA-I transgenic mice did not come in support of a class effect of HDL versus LDL. Thus, CETP activity was shown to be inhibited by native plasma HDL from wild-type mice but not by native plasma HDL from apoA-I transgenic mice, despite very similar affinities of CETP for either substrate (9). The latter observations rather come in support of an alternative hypothesis according to which a specific factor that is localized in HDL and not in LDL accounts for the inhibition of CETP activity.…”

Section: Differential Effects Of Hdl and Ldl On Cetp Activity-supporting

confidence: 63%

“…The latter observations rather come in support of an alternative hypothesis according to which a specific factor that is localized in HDL and not in LDL accounts for the inhibition of CETP activity. This specific inhibitor would be displaced from the HDL surface as a result of apoA-I overexpression in transgenic animals (9).…”

Section: Differential Effects Of Hdl and Ldl On Cetp Activity-mentioning

confidence: 99%

“…The resulting blots were blocked overnight at 4°C with 10% low fat dried milk in TBS containing 0.1% Tween, and washed with TBS-Tween. The blots were developed by successive incubations with affinity-purified anti-apoC-I antibodies (Biodesign) and with peroxidase-conjugated anti-goat antibodies (Sigma) as described previously (9). Blots were finally developed using an ECL kit (Amersham Pharmacia Biotech).…”

Section: Western Blot Analysesmentioning

confidence: 99%

“…In fact, the quest for a CETP inhibitor in plasma HDL over the last decade led to inconsistent observations, and no clear identification and characterization of an inhibitory protein in human HDL has been provided so far. Comparative studies of the ability of HDL from control mice and transgenic mice expressing human HDL apolipoproteins revealed that the lipid transfer-inhibitory activity associated with control mouse HDL can be completely lost as the result of the apoA-I and apoA-II overexpression in the transgenic mouse models (9). It appears therefore that neither apoA-I nor apoA-II can account for the strong inhibitory activity associated with plasma HDL, and observations in transgenic animals strongly support the existence of a distinct inhibitor protein in the HDL fraction.…”

mentioning

confidence: 99%

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Human Apolipoprotein C-I Accounts for the Ability of Plasma High Density Lipoproteins to Inhibit the Cholesteryl Ester Transfer Protein Activity

Gautier¹,

Masson²,

Barros³

et al. 2000

Journal of Biological Chemistry

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117

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The aim of the present study was to identify the protein that accounts for the cholesteryl ester transfer protein (CETP)-inhibitory activity that is specifically associated with human plasma high density lipoproteins (HDL). To this end, human HDL apolipoproteins were fractionated by preparative polyacrylamide gradient gel electrophoresis, and 30 distinct protein fractions with molecular masses ranging from 80 down to 2 kDa were tested for their ability to inhibit CETP activity. One single apolipoprotein fraction was able to completely inhibit CETP activity. The N-terminal sequence of the 6-kDa protein inhibitor matched the N-terminal sequence of human apoC-I, the inhibition was completely blocked by specific anti-apolipoprotein C-I antibodies, and mass spectrometry analysis confirmed the identity of the isolated inhibitor with full-length human apoC-I. Pure apoC-I was able to abolish CETP activity in a concentration-dependent manner and with a high efficiency (IC 50 ‫؍‬ 100 nmol/liter). The inhibitory potency of total delipidated HDL apolipoproteins completely disappeared after a treatment with anti-apolipoprotein C-I antibodies, and the apoC-I deprivation of native plasma HDL by immunoaffinity chromatography produced a mean 43% rise in cholesteryl ester transfer rates. The main localization of apoC-I in HDL and not in low density lipoprotein in normolipidemic plasma provides further support for the specific property of HDL in inhibiting CETP activity.Cholesteryl ester transfer protein (CETP), 1 a member of the lipid transfer/lipopolysaccharide-binding protein family promotes the exchange of neutral lipid species, i.e. cholesteryl esters and triglycerides, between plasma lipoproteins. In addition to the concentration of CETP in the plasma compartment, a number of other parameters, including the concentration and composition of lipoprotein substrates, can affect the velocity and the extent of the CETP-mediated neutral lipid transfer reaction. In earlier kinetic studies, Barter and Jones (1) and Ihm and colleagues (2) reported that the interactions of CETP with low density lipoproteins (LDL) versus high density lipoproteins (HDL) markedly differ. Hence, at a constant amount of HDL, the rate of the CETP-mediated cholesteryl ester exchange rises with increasing amounts of LDL until a maximal constant value is reached with high LDL to HDL cholesteryl ester ratios. Although at a fixed amount of LDL the rate of cholesteryl ester exchange also tended to increase with moderate amounts of HDL, a potent and significant inhibition of the CETP-mediated lipid transfer process was observed with higher HDL/LDL cholesterol ratios (1, 2). Initially, the inhibitory effect of HDL has been explained in terms of a greater interaction of CETP with HDL than with LDL, favoring the HDL-HDL exchanges over the LDL-HDL exchanges (1, 2). More recently, purified HDL apolipoproteins were shown to modulate the cholesteryl ester transfer reaction, and in particular apoA-I and apoA-II; i.e. the two major HDL apolipoproteins were alternatively des...

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Section: Differential Effects Of Hdl and Ldl On Cetp Activity-supporting

confidence: 63%

Section: Differential Effects Of Hdl and Ldl On Cetp Activity-mentioning

confidence: 99%

Section: Western Blot Analysesmentioning

confidence: 99%

mentioning

confidence: 99%

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Human Apolipoprotein C-I Accounts for the Ability of Plasma High Density Lipoproteins to Inhibit the Cholesteryl Ester Transfer Protein Activity

Gautier¹,

Masson²,

Barros³

et al. 2000

Journal of Biological Chemistry

Self Cite

117

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“…The resulting blots were blocked for 30 min at 37°C in 3% low fat dried milk in Tris-buffered saline containing 0.1% Tween, and they were washed in Tris-buffered saline/Tween. CETP was revealed by successive incubations with TP1 anti-CETP antibodies (Heart Institute, Ottawa, Canada) and horseradish peroxidase-coupled second antibodies as described previously (36). Blots were finally developed with an ECL kit (Amersham Biosciences).…”

Section: Methodsmentioning

confidence: 99%

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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Apolipoprotein A‐II

Escolà‐Gil

Martín‐Campos

Julve

et al. 2007

High‐Density Lipoproteins

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Differential Interaction of the Human Cholesteryl Ester Transfer Protein with Plasma High Density Lipoproteins (HDLs) from Humans, Control Mice, and Transgenic Mice to Human HDL Apolipoproteins

Cited by 13 publications

References 49 publications

Human Apolipoprotein C-I Accounts for the Ability of Plasma High Density Lipoproteins to Inhibit the Cholesteryl Ester Transfer Protein Activity

Human Apolipoprotein C-I Accounts for the Ability of Plasma High Density Lipoproteins to Inhibit the Cholesteryl Ester Transfer Protein Activity

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

Apolipoprotein A‐II

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