This Article Full Text Full Text (PDF) All Versions of this Article: 26/4/884    most recent 01.ATV.0000201064.89581.35v1 Submit a response 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 Kee, P. Articles by Barter, P.J. Search for Related Content PubMed PubMed Citation Articles by Kee, P. Articles by Barter, P.J. Related Collections Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:884.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effect of Inhibiting Cholesteryl Ester Transfer Protein on the Kinetics of High-Density Lipoprotein Cholesteryl Ester Transport in Plasma

In Vivo Studies in Rabbits

P. Kee; D. Caiazza; K.-A. Rye; P.H.R. Barrett; L.A. Morehouse; P.J. Barter

From Royal Adelaide Hospital (P.K.), Adelaide, Australia; The Heart Research Institute (D.C., K.-A.R., P.J.B.), Sydney, Australia; University of Sydney (K.-A.R., P.J.B.), Australia; University of Melbourne (K.-A.R.), Australia; University of Western Australia (P.H.R.B.), Australia; Pfizer Global Research and Development (L.A.M.), Groton, Conn.

Correspondence to Philip Barter, The Heart Research Institute, 145 Missenden Road, Camperdown, New South Wales, Australia 2050. E-mail barterp{at}hri.org.au

Objective— Inhibitors of cholesteryl ester transfer protein (CETP) have been developed as potential anti-atherogenic agents. Theoretically, however, they may be pro-atherogenic by blocking one of the pathways for removing high-density lipoprotein (HDL) cholesteryl esters (CE) from plasma in the final step of reverse cholesterol transport. Here we describe how CETP inhibition in rabbits impacts on the kinetics of HDL CE transport in plasma.

Methods and Results— Administration of a CETP inhibitor reduced CETP activity by 80% to 90% and doubled the HDL cholesteryl ester concentration. Multi-compartmental analysis was used to determine HDL CE kinetics in CETP-inhibited and control rabbits after injection of tracer amounts of both native and reconstituted HDL labeled with ³H in the CE moiety. In control rabbits, HDL CE was removed from plasma by both a direct pathway and an indirect pathway after transfer of HDL CE to the very-low-density lipoprotein/low-density lipoprotein fraction. In CETP-inhibited rabbits there was an almost complete block in removal via the indirect pathway. This did not compromise the overall removal of HDL CE from plasma, which was not different in control and inhibited animals.

Conclusion— Inhibiting CETP in rabbits does not compromise the removal of HDL CE from plasma.

An 80% to 90% inhibition of plasma CETP activity in rabbits doubled the concentration of HDL CE by blocking its transfer to the VLDL/LDL fraction. However, this did not compromise the removal of HDL CE from plasma.

Key Words: cholesteryl esters • high-density lipoprotein • inhibitor • kinetics • reverse cholesterol transport

Related Article:

Cholesteryl Ester Transfer Protein Inhibition: Effect on Reverse Cholesterol Transport?

Patrick C.N. Rensen and Louis M. Havekes
Arterioscler Thromb Vasc Biol 2006 26: 681-684. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. J. Nicholls, E. M. Tuzcu, D. M. Brennan, J.-C. Tardif, and S. E. Nissen Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis: Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) Circulation, December 9, 2008; 118(24): 2506 - 2514. [Abstract] [Full Text] [PDF]

				C. C. van der Hoogt, W. de Haan, M. Westerterp, M. Hoekstra, G. M. Dallinga-Thie, J. A. Romijn, H. M. G. Princen, J. W. Jukema, L. M. Havekes, and P. C. N. Rensen Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression J. Lipid Res., August 1, 2007; 48(8): 1763 - 1771. [Abstract] [Full Text] [PDF]

				L. A. Morehouse, E. D. Sugarman, P.-A. Bourassa, T. M. Sand, F. Zimetti, F. Gao, G. H. Rothblat, and A. J. Milici Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits J. Lipid Res., June 1, 2007; 48(6): 1263 - 1272. [Abstract] [Full Text] [PDF]

				M. Westerterp, C. C. van der Hoogt, W. de Haan, E. H. Offerman, G. M. Dallinga-Thie, J. W. Jukema, L. M. Havekes, and P. C.N. Rensen Cholesteryl Ester Transfer Protein Decreases High-Density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2552 - 2559. [Abstract] [Full Text] [PDF]

				P. C.N. Rensen and L. M. Havekes Cholesteryl Ester Transfer Protein Inhibition: Effect on Reverse Cholesterol Transport? Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 681 - 684. [Full Text] [PDF]