title: Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism.
abstract: Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D(3)-leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. jsmillar@mail.med.upenn.edu
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Brousseau
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Diffenderfer
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: Francine K
authors.initials: FK
authors.lastname: Welty
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Cohn
authors.forename: Aisha
authors.initials: A
authors.lastname: Wilson
authors.forename: Megan L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Chorthip
authors.initials: C
authors.lastname: Nartsupha
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schaefer
authors.forename: Andres G
authors.initials: AG
authors.lastname: Digenio
authors.forename: James P
authors.initials: JP
authors.lastname: Mancuso
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Dolnikowski
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000378:metabolism*; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D007700:Kinetics; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D016037:Single-Blind Method
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin