Abstract 575: ApoE Determines the Functional Fate of ApoC-III: Hepatic Clearance vs. Lipase Activity

Abstract

Clearance of triglyceride (TG)-rich lipoproteins (TRLs) is mediated by three main receptors syndecan-1 (SDC1), low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). Previous studies revealed that interactions of apolipoprotein (apo) E and apoA-V on TRLs with heparan sulfate chains of SDC1 are required for TLR clearance. ApoC-III is another apolipoprotein and emerging factor in regulating TG metabolism. We recently showed that apoC-III inhibits hepatic TRL clearance through the LDLR/LRP1 axis and that apoC-III accumulates on TRLs in mutant mice lacking functional SDC1 ( Ndst1 f/f Alb-Cre + ), suggesting that apoC-III enriched TRLs are preferentially cleared by SDC1. In this study we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism. In Apoe -/- Ndst1 f/f Alb-Cre + mice antisense oligonucleotide (ASO) lowering of apoC-III reduced plasma TG levels. In contrast to Ndst1 f/f Alb-Cre + mice the apoC-III ASO was not associated with improved hepatic TRL clearance in [ 3 H]retinol excursion studies in Apoe -/- Ndst1 f/f Alb-Cre + mice. Binding and uptake experiments in primary hepatocytes with apoE-deficient TRLs were not affected by the presence or absence of apoC-III. Reconstitution of the same TRLs with apoE inhibited clearance only of apoC-III enriched TRLs indicating that apoE is essential for apoC-III-mediated inhibition of TRL clearance. Further analysis revealed that apoC-III ASO improved lipase activity in Apoe -/- Ndst1 f/f Alb-Cre + mice. It remains to be determined if apoC-III lowering in the absence of apoE stimulates lipoprotein lipase or hepatic lipase or both. In conclusion we demonstrate that apoC-III blocks TRL clearance in an apoE-dependent manner and inhibits lipase activity in the absence of functional apoE.