Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP

https://doi.org/10.1016/j.jsb.2016.02.016Get rights and content
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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.

Abbreviations

AUC
analytical ultracentrifugation
apoA1
apolipoprotein A1
apoB
apolipoprotein B
CE
cholesteryl ester
CETP
cholesteryl ester transfer protein
CVD
cardiovascular disease
Fab
fragment antigen binding
GST
glutathione S-transferase
HDL
high-density lipoprotein
LDL
low-density lipoprotein
mAb
monoclonal antibody
KD
dissociation constant
SEC
size exclusion chromatography
SPR
surface plasmon resonance
TEM
transmission electron microscopy
VLDL
very low density lipoprotein

Keywords

Cholesterol transport
Electron microscopy
HDL
LDL
Cholesteryl ester transfer protein
HDL remodeling

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1

These authors contributed equally to this work.