title: Effects of CETP inhibition on triglyceride-rich lipoprotein composition and apoB-48 metabolism.
abstract: Cholesteryl ester transfer protein (CETP) facilitates the transfer of HDL cholesteryl ester to triglyceride-rich lipoproteins (TRL). This study aimed to determine the effects of CETP inhibition with torcetrapib on TRL composition and apoB-48 metabolism. Study subjects with low HDL cholesterol (<40 mg/dl), either untreated (n = 9) or receiving atorvastatin 20 mg daily (n = 9), received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for the next 4 weeks. A subset of the subjects not treated with atorvastatin participated in a third phase (n = 6), in which they received torcetrapib 120 mg twice daily for an additional 4 weeks. At the end of each phase, all subjects received a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine, while in the constantly fed state, to determine the kinetics of TRL apoB-48 and TRL composition. Relative to placebo, torcetrapib markedly reduced TRL CE levels in all groups (≥-69%; P < 0.005). ApoB-48 pool size (PS) and production rate (PR) decreased in the nonatorvastatin once daily (PS: -49%, P = 0.007; PR: -49%, P = 0.005) and twice daily (PS: -30%, P = 0.01; PR: -27%, P = 0.13) cohorts. In the atorvastatin cohort, apoB-48 PS and PR, which were already lowered by atorvastatin, did not change with torcetrapib. Our findings indicate that CETP inhibition reduced plasma apoB-48 concentrations by reducing apoB-48 production but did not have this effect in subjects already treated with atorvastatin.
authors.affiliation: Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Diffenderfer
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Brousseau
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: Chorthip
authors.initials: C
authors.lastname: Nartsupha
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schaefer
authors.forename: Megan L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Dolnikowski
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
mesh_terms: D053283:Apolipoprotein B-48 / Q000097:blood / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology; D014280:Triglycerides
chemical_list: D053283:Apolipoprotein B-48; D053480:Cholesterol Ester Transfer Proteins; D008074:Lipoproteins; D011804:Quinolines; D014280:Triglycerides; C483909:torcetrapib