Control of LDL Uptake in Human Cells by Targeting the LDLR Regulatory Long Non-coding RNA BM450697.
Galnac
LDL
LDLR
cholesterol
hypercholesterolemia
lncRNA
siRNA
transcriptional gene silencing
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
06 Sep 2019
06 Sep 2019
Historique:
received:
15
02
2019
revised:
29
05
2019
accepted:
29
05
2019
pubmed:
7
7
2019
medline:
7
7
2019
entrez:
7
7
2019
Statut:
ppublish
Résumé
Hypercholesterolemia is a condition that is characterized by very high levels of cholesterol in the blood and is a major correlating factor with heart disease. Indeed, high levels of the low-density lipoprotein (LDL) have been causally linked to the development of atherosclerotic cardiovascular disease (ASCVD). A method to specifically reduce cholesterol in the blood in a long-term, stable manner could prove therapeutically relevant. Cholesterol is removed from the blood by the LDL receptor (LDLR) in the liver. Others and we have discovered that a long non-coding RNA (lncRNA; BM450697) functions as an endogenous epigenetic regulator of LDLR and that the repression of this lncRNA by the action of small interfering RNAs (siRNAs) results in the activation of LDLR. We found here, through the interrogation of two siRNAs that can target this lncRNA, both in a transcriptional and post-transcriptional manner, that BM450697 functions as a local scaffold for modulating LDLR transcription. Moreover, we found that conjugation of α-N-acetylgalactosamine (GalNAc) with two lncRNA-directed siRNAs allows for direct liver cell targeting of this lncRNA and functional enhanced uptake of cholesterol. Collectively, these data suggest that targeting the BM450697 lncRNA regulator of LDLR may result in a more specific, long-term, targeted approach to regulating cholesterol in the blood.
Identifiants
pubmed: 31279228
pii: S2162-2531(19)30155-6
doi: 10.1016/j.omtn.2019.05.024
pmc: PMC6611981
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
264-276Subventions
Organisme : NIAID NIH HHS
ID : R01 AI111139
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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