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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:268.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Torcetrapib Differentially Modulates the Biological Activities of HDL2 and HDL3 Particles in the Reverse Cholesterol Transport Pathway

Giovanna Catalano; Zélie Julia; Eric Frisdal; Benoit Vedie; Natalie Fournier; Wilfried Le Goff; M. John Chapman; Maryse Guerin

From INSERM UMRS551 (G.C., Z.J., E.F., W.L.G., M.J.C., M.G.), Hôpital de la Pitié, Paris; Université Pierre et Marie Curie–Paris6 (G.C., Z.J., E.F., W.L.G., M.J.C., M.G.), Hôpital de la Pitié, Paris; AP-HP, Hôpital Européen Georges Pompidou (B.V., N.F.), Service de biochimie, Paris; and Univ Paris-Sud (N.F.), UMR INRA 1154, UFR de Pharmacie, Châtenay-Malabry, France.

Correspondence to Dr Maryse Guerin, PhD, INSERM Unité 551, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail maryse.guerin{at}upmc.fr

Objective— Therapeutic strategies to raise low plasma HDL-cholesterol levels, with concomitant normalization of the intravascular metabolism, physicochemical properties, and antiatherogenic function of HDL particles, are a major focus in atherosclerosis prevention.

Methods and Results— Patients displaying Type IIB hyperlipidemia (n=14) and healthy controls (n=11) were recruited. After drug washout, dyslipidemic patients first received atorvastatin (10 mg/d) for 6 weeks and subsequently torcetrapib/atorvastatin (60/10 mg/d) for the same period. Partial CETP inhibition markedly reduced supranormal CE transfer rates to normal levels from HDL3 (–58%; P<0.0001) to apoB-lipoproteins; endogenous CE transfer rates from HDL2 to apoB-lipoproteins were markedly subnormal as compared to those in control subjects (10.7±0.9 versus 29.3±4.8 µgCE/h/mL plasma, respectively). Torcetrapib enhanced the subnormal capacity of HDL2 particles from dyslipidemic patients to mediate free cholesterol efflux via both SR-BI and ABCG1 pathways (+38%;P<0.003 and +35%;P<0.03, respectively) as compared to baseline. In vitro observations and in vivo studies in mice demonstrated that CETP inhibition was associated with an enhanced selective hepatic uptake of CE from HDL particles (1.7-fold; P<0.0003).

Conclusion— CETP inhibition partially corrected the abnormal physicochemical and functional properties of HDL2 and HDL3 particles in type IIB hyperlipidemia. Enhanced hepatic selective uptake of HDL-CE may compensate for attenuated indirect CE transfer to apoB-containing lipoproteins via CETP attributable to torcetrapib.

Key Words: CETP • torcetrapib • high density lipoprotein • cellular cholesterol efflux • HDL-CE uptake

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