Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men

Abstract

Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plasma of six normolipidemic men (mean age: 29.7 +/- 2.7 years) in the fasting state and after a five-hour intravenous infusion with a synthetic TG emulsion, Intralipid. Intralipid infusion resulted in a 2.1-fold increase in the TG content of HDL. Each tracer was then whole-labeled with 125I or 131I and injected intravenously into the subject. Apo A-I in TG-enriched HDL was cleared 26% more rapidly than apo A-I in fasting HDL. A strong correlation between the Intralipid-induced increase in the TG content of HDL and the increase in HDL apo A-I fractional catabolic rate reinforced the importance of TG enrichment of HDL in enhancing its metabolic clearance. HDL was separated further into lipoproteins containing apo A-II (LpAI:AII) and those without apo A-II (LpAI). Results revealed that the enhanced clearance of apo A-I from TG-enriched HDL could be largely attributed to differences in the clearance of LpAI but not LpAI:AII. This is, to our knowledge, the first direct demonstration in humans that TG enrichment of HDL enhances the clearance of HDL apo A-I from the circulation. This phenomenon could provide an important mechanism explaining how HDL apo A-I and HDL cholesterol are lowered in hypertriglyceridemic states.

Figure 1

Relative proportion, in percent, of phosphatidylcholine (PC), sphingomyelin (SM), and lysophosphatidylcholine (LPC) in fasting and TG-enriched HDL tracers. Values are expressed as a percentage of all three phospholipid subclasses. This analysis was performed on a second sample of six normolipidemic subjects to characterize further the phospholipid content of HDL with Intralipid infusion (see Methods). The plasma lipid profile of these six subjects was similar to that of the six individuals who participated in the HDL turnover study.

Figure 2

Mean die-away curves of apo A-I radioactivity from fasting and TG-enriched HDL in six human participants. The data presented on the y axis represent the radioactivity on HDL apo A-I isolated by gel electrophoresis of the delipidated HDL fraction (see Methods). The radioactivity data for each tracer were first expressed as a specific activity and then normalized as a function of the radioactivity measured at the first time interval (10 min). The curves were generated by fitting a two-pool model (two-exponential function) to the data. Values are mean ± SEM.

Figure 3

Correlation between the Intralipid-induced -fold increase in the TG content of HDL and the simultaneous increase in HDL apo A-I FCR. A similar correlation with the increased HDL apo A-I FCR was observed when changes in the TG content of HDL after the five-hour Intralipid infusion were expressed as changes in percent rather than -fold increase (r = 0.80, P = 0.05; not shown). The correlation was obtained using the -fold increase in the TG content of HDL of the radiolabeled (injected) tracer.