Evaluation of CETP activity in vivo under non-steadystate 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 fl ux 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 specifi c 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 fl ux. Based on our data, we estimate that the peak total postprandial TG fl ux to HDL via CETP is 13mg•h-1 •kg-1and 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.