title: Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux.
abstract: Studies in lipoprotein kinetics almost exclusively rely on steady-state approaches to modeling. Herein, we have used a non-steady-state experimental design to examine the role of cholesteryl ester transfer protein (CETP) in mediating HDL-TG flux in vivo in rhesus macaques, and therefore, we developed an alternative strategy to model the data. Two isotopomers ([(2)H11] and [(13)C18]) of oleic acid were administered (orally and intravenously, respectively) to serve as precursors for labeling TGs in apoB-containing lipoproteins. The flux of a specific TG (52:2) from these donor lipoproteins to HDL was used as the measure of CETP activity; calculations are also presented to estimate total HDL-TG flux. Based on our data, we estimate that the peak total postprandial TG flux to HDL via CETP is ∼ 13 mg · h(-1) · kg(-1) and show that this transfer was inhibited by 97% following anacetrapib treatment. Collectively, these data demonstrate that HDL TG flux can be used as a measure of CETP activity in vivo. The fact that the donor lipoproteins can be labeled in situ using well-established stable isotope tracer techniques suggests ways to measure this activity for native lipoproteins in free-living subjects under any physiological conditions.
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033 david_mclaren@merck.com.
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.affiliation: Integrative Bioinformatics Inc., Mountain View, CA 94041.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Phair
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stout
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Suoyu S
authors.initials: SS
authors.lastname: Xu
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Castro-Perez
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Opiteck
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Karen O
authors.initials: KO
authors.lastname: Akinsanya
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Hayes M
authors.initials: HM
authors.lastname: Dansky
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ 07033.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
mesh_terms: D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008954:Models, Biological; D023303:Oxazolidinones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D023303:Oxazolidinones; D014280:Triglycerides; C530884:anacetrapib
keywords: ProcessDB; cholesteryl ester transfer protein; high density lipoprotein; lipoproteins; non-steady-state dynamics; postprandial; rhesus macaques; triglyceride