HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 45, 38108-38116, November 11, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/45/38108    most recent M504678200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dumont, L. Articles by Lagrost, L. Search for Related Content PubMed PubMed Citation Articles by Dumont, L. Articles by Lagrost, L. Social Bookmarking                      What's this?

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

Laure Dumont1, Thomas Gautier1, Jean-Paul Pais de Barros, Hélène Laplanche, Denis Blache, Patrick Ducoroy, Jamila Fruchart¶, Jean-Charles Fruchart¶, Philippe Gambert, David Masson2, and Laurent Lagrost3

From the Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Faculté deMédecine, BP87900, 21079 Dijon Cedex, France, the Institut Fédératif de Recherche 100, Faculté deMédecine, BP87900, 21079 Dijon Cedex, and ^¶INSERM U545, Institut Pasteur, BP245, 59019 Lille Cedex, France

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.

Received for publication, April 28, 2005 , and in revised form, September 12, 2005.

^* This work was supported by an International HDL Research Awards Program grant (to L. L.), INSERM, the Conseil Régional de Bourgogne, and the Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 33-3-80-39-32-63; Fax: 33-3-80-39-34-47; E-mail: david.masson{at}chu-dijon.fr.

³ To whom correspondence may be addressed. Tel.: 33-3-80-39-32-63; Fax: 33-3-80-39-34-47; E-mail: laurent.lagrost{at}u-bourgogne.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. He, D. J. Greene, M. Kinter, and R. E. Morton Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex J. Lipid Res., July 1, 2008; 49(7): 1529 - 1537. [Abstract] [Full Text] [PDF]

				D. Masson, J.-P. Pais de Barros, Z. Zak, T. Gautier, N. Le Guern, M. Assem, J. W. Chisholm, J. R. Paterniti Jr., and L. Lagrost Human apoA-I expression in CETP transgenic rats leads to lower levels of apoC-I in HDL and to magnification of CETP-mediated lipoprotein changes J. Lipid Res., February 1, 2006; 47(2): 356 - 365. [Abstract] [Full Text] [PDF]