Abstract 674: Effects of ApoE on Metabolism of ApoB Lipoproteins Are Antagonized by ApoC3: A Kinetic Study in Humans
We aim to identify mechanisms by which apolipoprotein E (apoE) and apoC3 affect the metabolism of apoB lipoproteins in vivo in humans. Kinetics of apoB lipoproteins were studied in the fasting state in 5 hypertriglyceridemic and 6 normolipidemic participants by endogenous labeling of D3-Leucine and D5-Phenylalanine. Plasma samples were first separated by immuno-affinity columns according to apoE and apoC3, were further separated by ultracentrifugation into light and dense VLDL, IDL and 3 LDL subfractions, and the tracer-tracee ratio and mass data were analyzed by multi-compartmental modeling. Results showed that VLDL and IDL with apoE had 50%±150% faster fractional catabolic rates (FCR) than those without apoE but only in particles that did not have apoC3. Flux analysis also revealed distinct patterns of metabolism according to apoE in VLDL and IDL without apoC3: while 95% of particles without apoE and apoC3 were lipolyzed to LDL, 90% of those with apoE but not apoC3 underwent direct clearance. On the other hand, when apoC3 was present on VLDL and IDL, particles with and without apoE had similar FCR. However, those with apoE were still more likely to be directly removed from circulation instead of being lipolyzed to smaller lipoproteins. Our results also demonstrated that lipolysis was often associated with complete loss of apoC3 or apoE. For example, more than 80% of LDL with apoE and apoC3 underwent a stepwise loss of apoE and then apoC3 to form the main type of LDL: those without apoE and apoC3. Surprisingly, apoB lipoproteins with apoC3 had faster FCR than those without apoC3, perhaps attributable to their 2±6 fold higher content of apoC2. Finally, compared to normolipidemics, hypertriglyceridemics had 2.5 fold higher rates of secretion of VLDL with apoC3, and 50%±70% slower FCR of VLDL and IDL. In conclusion, we find that apoE increases FCR of triglyceride-rich lipoproteins, an effect apparently antagonized by apoC3. Nonetheless, even when apoC3 is present, a residual effect of apoE is still evident by diverting particles from lipolysis to direct clearance. The unexpectedly high FCR of apoC3 containing particles could be related to their high apoC2 content, underscoring the complexity of the metabolism of apoB lipoproteins.