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

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/fAlb-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.

Source: The Journal of Lipid Research - July 31, 2019 Category: Lipidology Authors: Ramms, B., Patel, S., Nora, C., Pessentheiner, A. R., Chang, M. W., Green, C. R., Golden, G. J., Secrest, P., Krauss, R. M., Metallo, C. M., Benner, C., Alexander, V. J., Witztum, J. L., Tsimikas, S., Esko, J. D., Gordts, P. L. S. M. Tags: Research Articles Source Type: research