Torcetrapib differentially modulates the biological activities of HDL2 and HDL3 particles in the reverse cholesterol transport pathway.
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.


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 microg CE/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).


CONCLUSIONS
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.
Catalano
Giovanna
G
INSERM UMRS551, Hôpital de la Pitié, Paris, France.
Julia
Zélie
Z
Frisdal
Eric
E
Vedie
Benoit
B
Fournier
Natalie
N
Le Goff
Wilfried
W
Chapman
M John
MJ
Guerin
Maryse
M
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood; D000328:Adult; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000097:blood; D000069059:Atorvastatin; D045744:Cell Line, Tumor; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D004359:Drug Therapy, Combination; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy*; D053439:Lipoproteins, HDL2 / Q000097:blood*; D053440:Lipoproteins, HDL3 / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D051122:Scavenger Receptors, Class B / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome
C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053439:Lipoproteins, HDL2; D053440:Lipoproteins, HDL3; D011758:Pyrroles; D011804:Quinolines; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; C483909:torcetrapib; D000069059:Atorvastatin