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.
Highlights
Studies in lipoprotein kinetics almost exclusively rely on steady-state approaches to modeling
The largest change was in HDL-TG content, and this is consistent with reduced transfer from TG-rich lipoproteins such as VLDL and chylomicrons due to inhibition of cholesteryl ester transfer protein (CETP)
The observation that the enrichments in the VLDL and chylomicron fractions were comparable during both treatment paradigms whereas enrichments in the HDL fractions were substantially reduced following anacetrapib treatment suggested that the effects of anacetrapib on HDL-TG flux could be reasonably assessed using a strategy based on either intravenous or oral administration of tracer
Summary
Studies in lipoprotein kinetics almost exclusively rely on steady-state approaches to modeling. The flux of a specific TG (52:2) from these donor lipoproteins to HDL was used as the measure of CETP activity; calculations are presented to estimate total HDL-TG flux. We estimate that the peak total postprandial TG flux to HDL via CETP is ف13 mg·h؊1·kg؊1 and show that this transfer was inhibited by 97% following anacetrapib treatment. These data demonstrate that HDL TG flux can be used as a measure of CETP activity in vivo. Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux.
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