ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance

Abstract

Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased CVD risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDL receptor-mediated and LDL receptor-related protein 1-mediated hepatic TRL clearance and that apoC-III-enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe/Ndst1f/fAlb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe/Ndst1f/f Alb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe/Ndst1f/fAlb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue in the fed state. Finally, clinical data confirmed that ASO-mediated lowering of APOC-III via volanesorsen can reduce plasma TG levels independent of the APOE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that, in the absence of functional apoE, apoC-III inhibits tissue LPL activity.-Ramms, B., S. Patel, C. Nora, A. R. Pessentheiner, M. W. Chang, C. R. Green, G. J. Golden, P. Secrest, R. M. Krauss, C. M. Metallo, C. Benner, V. J. Alexander, J. L. Witztum, S. Tsimikas, J. D. Esko, and P. L. S. M. Gordts. ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance.