Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux[S]

• Published in: Journal of lipid research Vol. 57; no. 3; pp. 398 - 409
• Main Authors: McLaren, David G., Previs, Stephen F., Phair, Robert D., Stout, Steven J., Xie, Dan, Chen, Ying, Salituro, Gino M., Xu, Suoyu S., Castro-Perez, Jose M., Opiteck, Gregory J., Akinsanya, Karen O., Cleary, Michele A., Dansky, Hayes M., Johns, Douglas G., Roddy, Thomas P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2016; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol Ester Transfer Proteins - metabolism; cholesteryl ester transfer protein; high density lipoprotein; lipoproteins; Lipoproteins, HDL - blood; Lipoproteins, HDL - metabolism; Macaca mulatta; Male; Models, Biological; non-steady-state dynamics; Oxazolidinones - pharmacology; postprandial; ProcessDB; rhesus macaques; triglyceride; Triglycerides - blood; Triglycerides - metabolism; postprandial; triglyceride; rhesus macaques; cholesteryl ester transfer protein; non-steady-state dynamics; high density lipoprotein; ProcessDB; lipoproteins
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.M063842

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 ([2H11] and [13C18]) 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.