PCSK9 and LRP5 in macrophage lipid internalization and inflammation.
Atherosclerosis
/ enzymology
Biological Transport
Cells, Cultured
Cholesterol
/ metabolism
Foam Cells
/ enzymology
Humans
Immunity, Innate
Inflammation
/ enzymology
Lipid Metabolism
Lipoproteins, LDL
/ metabolism
Low Density Lipoprotein Receptor-Related Protein-5
/ genetics
Macrophages
/ enzymology
Monocytes
/ enzymology
NF-kappa B
/ metabolism
Proprotein Convertase 9
/ genetics
Signal Transduction
Sterol Regulatory Element Binding Protein 2
/ metabolism
Toll-Like Receptor 4
/ metabolism
Wnt3A Protein
Inflammation
Lipoproteins
Macrophages
PCSK9
lrp5
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
27 07 2021
27 07 2021
Historique:
received:
10
03
2020
revised:
26
06
2020
accepted:
15
09
2020
pubmed:
30
9
2020
medline:
8
2
2022
entrez:
29
9
2020
Statut:
ppublish
Résumé
Atherosclerosis, the leading cause of cardiovascular diseases, is driven by high blood cholesterol levels and chronic inflammation. Low-density lipoprotein receptors (LDLR) play a critical role in regulating blood cholesterol levels by binding to and clearing LDLs from the circulation. The disruption of the interaction between proprotein convertase subtilisin/kexin 9 (PCSK9) and LDLR reduces blood cholesterol levels. It is not well known whether other members of the LDLR superfamily may be targets of PCSK9. The aim of this work was to determine if LDLR-related protein 5 (LRP5) is a PCSK9 target and to study the role of PCSK9 and LRP5 in foam cell formation and lipid accumulation. Primary cultures of human inflammatory cells (monocytes and macrophages) were silenced for LRP5 or PCSK9 and challenged with LDLs. We first show that LRP5 is needed for macrophage lipid uptake since LRP5-silenced macrophages show less intracellular CE accumulation. In macrophages, internalization of LRP5-bound LDL is already highly evident after 5 h of LDL incubation and lasts up to 24 h; however, in the absence of both LRP5 and PCSK9, there is a strong reduction of CE accumulation indicating a role for both proteins in lipid uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in lipid-loaded macrophages. Finally, PCSK9 participates in TLR4/NFkB signalling; a decreased TLR4 protein expression levels and a decreased nuclear translocation of NFκB were detected in PCSK9 silenced cells after lipid loading, indicating a downregulation of the TLR4/NFκB pathway. Our results show that both LRP5 and PCSK9 participate in lipid uptake in macrophages. In the absence of LRP5, there is a reduced release of PCSK9 indicating that LRP5 also participates in the mechanism of release of soluble PCSK9. Furthermore, PCSK9 up-regulates TLR4/NFκB favouring inflammation.
Identifiants
pubmed: 32991689
pii: 5912934
doi: 10.1093/cvr/cvaa254
doi:
Substances chimiques
LRP5 protein, human
0
Lipoproteins, LDL
0
Low Density Lipoprotein Receptor-Related Protein-5
0
NF-kappa B
0
SREBF2 protein, human
0
Sterol Regulatory Element Binding Protein 2
0
TLR4 protein, human
0
Toll-Like Receptor 4
0
WNT3A protein, human
0
Wnt3A Protein
0
Cholesterol
97C5T2UQ7J
PCSK9 protein, human
EC 3.4.21.-
Proprotein Convertase 9
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2054-2068Subventions
Organisme : Spanish Ministry of Science and Innovation
Organisme : FEDER funds
ID : SAF2016-76819-R
Organisme : Instituto de Salud Carlos III
ID : CN16/11/00411
Organisme : Generalitat of Catalunya-Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat
ID : 2014SGR1303
Organisme : Spanish Society of Cardiology
ID : FEC2019
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.