Apolipoprotein CI is a physiological regulator of cholesteryl ester transfer protein activity in human plasma but not in rabbit plasma

Jean-Paul Pais De Barros,Aurélia Boualam,Thomas Gautier,Laure Dumont,Bruno Vergès,David Masson,Laurent Lagrost

doi:10.1194/jlr.m800588-jlr200

Abstract

Plasma cholesteryl ester transfer protein (CETP) activity is high in rabbits, intermediate in humans, and nondetectable in rodents. Human apolipoprotein CI (apoCI) was found to be a potent inhibitor of CETP. The aim of this study was to compare the ability of rabbit and human apoCI to modulate the interaction of CETP with HDLs and to evaluate to which extent apoCI contributes to plasma cholesteryl ester transfer rate in normolipidemic humans and rabbits. Rabbit apoCI gene was cloned and sequenced, rabbit and human apoCI were purified to homogeneity, and their ability to modify the surface charge properties and the CETP inhibitory potential of HDL were compared. It is demonstrated that unlike human apoCI, rabbit apoCI does not modulate cholesteryl ester transfer rate in total plasma. Whereas both human and rabbit apoCI readily associate with HDL, only human apoCI was found to modify the electrostatic charge of HDL. In humans, both CETP and apoCI at normal, physiological levels contribute significantly to the plasma cholesteryl ester transfer rate. In contrast, CETP is the sole major determinant of cholesteryl ester transfer in normolipidemic rabbit plasma as a result of the inability of rabbit apoCI to change HDL electronegativity.

Highlights

Plasma cholesteryl ester transfer protein (CETP) activity is high in rabbits, intermediate in humans, and nondetectable in rodents
On the other hand, purified human apolipoprotein CI (apoCI) is a potent inhibitor of cholesteryl ester transfer protein (CETP) activity when associated with HDL, and as such it has the ability to reduce the net mass transfer of cholesteryl esters from HDL toward VLDL [22, 23]
We demonstrate here that rabbit apoCI has no CETP inhibitory potential, while in turn, human apoCI is found for the first time to constitute a physiological and important contributor to cholesteryl ester transfer rates in healthy subjects

Summary

Introduction

Plasma cholesteryl ester transfer protein (CETP) activity is high in rabbits, intermediate in humans, and nondetectable in rodents. Whereas both human and rabbit apoCI readily associate with HDL, only human apoCI was found to modify the electrostatic charge of HDL In humans, both CETP and apoCI at normal, physiological levels contribute significantly to the plasma cholesteryl ester transfer rate. In vivo studies in animal models supported the hypothesis that apoCI plays a complex and significant role in both the accumulation of VLDL particles in the blood stream and the reduction in their cholesteryl ester content relative to triglycerides [14,15,16,17,18,19] This effect of apoCI on VLDL clearance has been shown to be of physiological relevance in humans [20, 21].

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