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

Autor:	Ramms B; Departments of Cellular and Molecular Medicine,University of California, San Diego, La Jolla, CA.; Medicine, University of California, San Diego, La Jolla, CA.; Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany., Patel S; Medicine, University of California, San Diego, La Jolla, CA., Nora C; Medicine, University of California, San Diego, La Jolla, CA., Pessentheiner AR; Medicine, University of California, San Diego, La Jolla, CA., Chang MW; Departments of Cellular and Molecular Medicine,University of California, San Diego, La Jolla, CA., Green CR; Bioengineering, University of California, San Diego, La Jolla, CA., Golden GJ; Departments of Cellular and Molecular Medicine,University of California, San Diego, La Jolla, CA.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA., Secrest P; Departments of Cellular and Molecular Medicine,University of California, San Diego, La Jolla, CA., Krauss RM; Children's Hospital Oakland Research Institute Oakland, CA., Metallo CM; Bioengineering, University of California, San Diego, La Jolla, CA., Benner C; Departments of Cellular and Molecular Medicine,University of California, San Diego, La Jolla, CA., Alexander VJ; Ionis Pharmaceuticals Inc., Carlsbad, CA., Witztum JL; Medicine, University of California, San Diego, La Jolla, CA., Tsimikas S; Medicine, University of California, San Diego, La Jolla, CA., Esko JD; Departments of Cellular and Molecular Medicine,University of California, San Diego, La Jolla, CA.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA., Gordts PLSM; Medicine, University of California, San Diego, La Jolla, CA pgordts@ucsd.edu.; Bioengineering, University of California, San Diego, La Jolla, CA.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2019 Aug; Vol. 60 (8), pp. 1379-1395. Date of Electronic Publication: 2019 May 14.
DOI:	10.1194/jlr.M093740
Abstrakt:	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 -/- Ndst1 f/f Alb-Cre + ). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe -/- Ndst1 f/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 -/- Ndst1 f/f Alb-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. (Copyright © 2019 Ramms et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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