title: Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages.
abstract: Liver X receptors (LXR) are oxysterol-activated nuclear receptors that play a central role in reverse cholesterol transport through up-regulation of ATP-binding cassette transporters (ABCA1 and ABCG1) that mediate cellular cholesterol efflux. Mouse models of atherosclerosis exhibit reduced atherosclerosis and enhanced regression of established plaques upon LXR activation. However, the coregulatory factors that affect LXR-dependent gene activation in macrophages remain to be elucidated. To identify novel regulators of LXR that modulate its activity, we used affinity purification and mass spectrometry to analyze nuclear LXRα complexes and identified poly(ADP-ribose) polymerase-1 (PARP-1) as an LXR-associated factor. In fact, PARP-1 interacted with both LXRα and LXRβ. Both depletion of PARP-1 and inhibition of PARP-1 activity augmented LXR ligand-induced ABCA1 expression in the RAW 264.7 macrophage line and primary bone marrow-derived macrophages but did not affect LXR-dependent expression of other target genes, ABCG1 and SREBP-1c. Chromatin immunoprecipitation experiments confirmed PARP-1 recruitment at the LXR response element in the promoter of the ABCA1 gene. Further, we demonstrated that LXR is poly(ADP-ribosyl)ated by PARP-1, a potential mechanism by which PARP-1 influences LXR function. Importantly, the PARP inhibitor 3-aminobenzamide enhanced macrophage ABCA1-mediated cholesterol efflux to the lipid-poor apolipoprotein AI. These findings shed light on the important role of PARP-1 on LXR-regulated lipid homeostasis. Understanding the interplay between PARP-1 and LXR may provide insights into developing novel therapeutics for treating atherosclerosis.
authors.affiliation: From the Department of Microbiology, New York University School of Medicine, New York, New York 10016.
authors.forename: Elina
authors.initials: E
authors.lastname: Shrestha
authors.affiliation: From the Department of Microbiology, New York University School of Medicine, New York, New York 10016.
authors.forename: Maryem A
authors.initials: MA
authors.lastname: Hussein
authors.affiliation: the Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Savas
authors.affiliation: the Department of Medicine, Division of Cardiology, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ouimet
authors.affiliation: the Department of Medicine, Division of Cardiology, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Tessa J
authors.initials: TJ
authors.lastname: Barrett
authors.affiliation: From the Department of Microbiology, New York University School of Medicine, New York, New York 10016.
authors.forename: Sarah
authors.initials: S
authors.lastname: Leone
authors.affiliation: the Department of Chemical Physiology, Scripps Research Institute, La Jolla, California 92037.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: the Department of Medicine, Division of Cardiology, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.affiliation: the Department of Medicine, Division of Cardiology, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: From the Department of Microbiology, New York University School of Medicine, New York, New York 10016, michael.garabedian@nyumc.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics; D000818:Animals; D001693:Biological Transport, Active; D002784:Cholesterol / Q000378:metabolism*; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D002784:Cholesterol; D000071518:Liver X Receptors; D000071137:Poly (ADP-Ribose) Polymerase-1; D011994:Recombinant Proteins; D051780:Sterol Regulatory Element Binding Protein 1; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C497388:Srebf1 protein, mouse; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse
keywords: ABC transporter; ABCA1; ADP-ribosylation; LXR; PARP-1; atherosclerosis; cholesterol regulation; gene expression; nuclear receptor; transcription corepressor