EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux

The sterol-responsive nuclear receptors, liver X receptors α (LXRα, ) and β (LXRβ, ), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters and to promote efflux of exces...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Arteriosclerosis, thrombosis, and vascular biology Jg. 37; H. 3; S. 423 - 432
Hauptverfasser: Nelson, Jessica Kristine, Koenis, Duco Steven, Scheij, Saskia, Cook, Emma Clare Laura, Moeton, Martina, Santos, Ana, Lobaccaro, Jean-Marc Adolphe, Baron, Silvere, Zelcer, Noam
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.03.2017
Schlagworte:
Animals
Apolipoprotein A-I - metabolism
ATP Binding Cassette Transporter 1 - genetics
ATP Binding Cassette Transporter 1 - metabolism
Biological Transport
Cell Membrane - drug effects
Cell Membrane - enzymology
Chlorocebus aethiops
Cholesterol - metabolism
COS Cells
Endodeoxyribonucleases - genetics
Endodeoxyribonucleases - metabolism
Gene Expression Profiling - methods
Gene Expression Regulation, Enzymologic
HeLa Cells
Hep G2 Cells
Humans
Ligands
Liver X Receptors - agonists
Liver X Receptors - deficiency
Liver X Receptors - genetics
Liver X Receptors - metabolism
Macrophages - drug effects
Macrophages - enzymology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
RAW 264.7 Cells
RNA Interference
Transcriptome
Transfection
ABCA1
nuclear receptors
macrophages
cholesterol efflux
cholesterol metabolism
LXR
ISSN:1524-4636
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:The sterol-responsive nuclear receptors, liver X receptors α (LXRα, ) and β (LXRβ, ), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters and to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study. We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease-exonuclease-phosphatase family domain containing 1 ( ) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression of blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages. In this study, we identify as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1524-4636
DOI:10.1161/ATVBAHA.116.308434