title: An LXR-NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux.
abstract: LXR-cofactor complexes activate the gene expression program responsible for cholesterol efflux in macrophages. Inflammation antagonizes this program, resulting in foam cell formation and atherosclerosis; however, the molecular mechanisms underlying this antagonism remain to be fully elucidated. We use promoter enrichment-quantitative mass spectrometry (PE-QMS) to characterize the composition of gene regulatory complexes assembled at the promoter of the lipid transporter Abca1 following downregulation of its expression. We identify a subset of proteins that show LXR ligand- and binding-dependent association with the Abca1 promoter and demonstrate they differentially control Abca1 expression. We determine that NCOA5 is linked to inflammatory Toll-like receptor (TLR) signaling and establish that NCOA5 functions as an LXR corepressor to attenuate Abca1 expression. Importantly, TLR3-LXR signal crosstalk promotes recruitment of NCOA5 to the Abca1 promoter together with loss of RNA polymerase II and reduced cholesterol efflux. Together, these data significantly expand our knowledge of regulatory inputs impinging on the Abca1 promoter and indicate a central role for NCOA5 in mediating crosstalk between pro-inflammatory and anti-inflammatory pathways that results in repression of macrophage cholesterol efflux.
authors.affiliation: Institute for Systems Biology, Seattle, WA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gillespie
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gold
authors.affiliation: Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ramsey
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Podolsky
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.affiliation: Institute for Systems Biology, Seattle, WA, USA jeff.ranish@systemsbiology.org.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ranish
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056918:Nuclear Receptor Coactivators / Q000235:genetics* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D000071518:Liver X Receptors; D056918:Nuclear Receptor Coactivators; D057093:Orphan Nuclear Receptors; D012319:RNA Polymerase II; D051196:Toll-Like Receptor 3; C577833:Abca1 protein, mouse; C000599519:NCOA5 protein, mouse; C519703:TLR3 protein, mouse
keywords: LXR; NCOA5; atherosclerosis; inflammation; quantitative mass spectrometry