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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ramms, B; Patel, S; Nora, C; Pessentheiner, AR; Chang, MW; Green, CR; Golden, GJ; Secrest, P; Krauss, RM; Metallo, CM; Benner, C; Alexander, VJ; Witztum, JL; Tsimikas, S; Esko, JD; Gordts, PLSM.
ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance.
J Lipid Res. 2019; 60(8): 1379-1395.
Doi: 10.1194/jlr.M093740
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- Co-Autor*innen der Med Uni Graz
- Pessentheiner Ariane Raphaela
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- 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/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. Copyright © 2019 Ramms et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apolipoprotein C-III - genetics
- Apolipoprotein C-III - metabolism
- Apolipoproteins E - deficiency
- Lipoprotein Lipase - genetics
- Lipoprotein Lipase - metabolism
- Mice -
- Mice, Knockout, ApoE -
- Receptors, LDL - genetics
- Receptors, LDL - metabolism
- Triglycerides - blood
- Find related publications in this database (Keywords)
- lipid metabolism
- apolipoprotein C-III
- apolipoprotein E
- triglyceride-rich lipoprotein clearance
- fatty acids
- lipase
- lipoprotein lipase