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...

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Vydáno v:	Arteriosclerosis, thrombosis, and vascular biology Ročník 37; číslo 3; s. 423 - 432
Hlavní autoři:	Nelson, Jessica Kristine, Koenis, Duco Steven, Scheij, Saskia, Cook, Emma Clare Laura, Moeton, Martina, Santos, Ana, Lobaccaro, Jean-Marc Adolphe, Baron, Silvere, Zelcer, Noam
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.03.2017
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1524-4636
DOI:	10.1161/ATVBAHA.116.308434