title: Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP.
abstract: The cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester (CE) from high-density lipoproteins (HDL) to low-density lipoproteins (LDL) in the plasma compartment. CETP inhibition raises plasma levels of HDL cholesterol; a ternary tunnel complex with CETP bridging HDL and LDL was suggested as a mechanism. Here, we test whether the inhibition of CETP tunnel complex formation is a promising approach to suppress CE transfer from HDL to LDL, for potential treatment of cardio-vascular disease (CVD). Three monoclonal antibodies against different epitopes of CETP are assayed for their potential to interfere with CE transfer between HDL and/or LDL. Surprisingly, antibodies that target the tips of the elongated CETP molecule, interaction sites sterically required to form the suggested transfer complexes, do not interfere with CETP activity, but an antibody binding to the central region does. We show that CETP interacts with HDL, but not with LDL. Our findings demonstrate that a ternary tunnel complex is not the mechanistic prerequisite to transfer CE among lipoproteins.
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Lauer
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Graff-Meyer
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Arne C
authors.initials: AC
authors.lastname: Rufer
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Maugeais
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: von der Mark
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Matile
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: D'Arcy
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland; Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Magg
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ringler
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Müller
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Scherer
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dernick
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Thoma
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland; Current address: LeadXpro AG, CH-5234 Villigen, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.affiliation: Pharma Research and Early Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: Eric.Niesor@bluewin.ch.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Niesor
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland. Electronic address: Henning.Stahlberg@unibas.ch.
authors.forename: Henning
authors.initials: H
authors.lastname: Stahlberg
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000302:isolation & purification; D001692:Biological Transport; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D002788:Cholesterol Esters / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry* / Q000648:ultrastructure; D015870:Gene Expression; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000648:ultrastructure; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000911:Antibodies, Monoclonal; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D000939:Epitopes; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins
keywords: Cholesterol transport; Cholesteryl ester transfer protein; Electron microscopy; HDL; HDL remodeling; LDL