@article{8096c405569c4e459f426afda235502d,
title = "LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux",
abstract = "The activation of liver X receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying the repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of activator protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while the direct repressive functions of LXR also play a key role but are independent of AP-1. We use assay for transposase-accessible chromatin using sequencing (ATAC-seq) to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with the induction of LXR targets mediating cholesterol efflux.",
keywords = "LXR, cholesterol, cholesterol efflux, cis-repression, liver X receptor, neutrophil migration, nuclear receptor, oxysterol, peritonitis, transrepression",
author = "Thomas, {David G.} and Doran, {Amanda C.} and Panagiotis Fotakis and Marit Westerterp and Per Antonson and Hui Jiang and Jiang, {Xian Cheng} and Gustafsson, {Jan {\AA}ke} and Ira Tabas and Tall, {Alan R.}",
note = "Funding Information: We thank S. Ghosh, N. Wang, and M. Reilly for helpful discussions. This work was supported by grants from the NIH (HL107653 to A.R.T.; HL132412, HL075662, and HL127464 to I.T.; and HL137327 to D.G.T.), the Swedish Science Council, Swedish CIMED grant, the Robert A. Welch Foundation (E-0004 to J.-A.G.), the Netherlands Organization for Scientific Research (VIDI grant 917.15.350 to M.W.), and the UMCG (Rosalind Franklin Fellowship to M.W.). Research reported in this publication was performed in the CCTI Flow Cytometry Core, which is supported in part by the Office of the Director, NIH under award S10RR027050. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: We thank S. Ghosh, N. Wang, and M. Reilly for helpful discussions. This work was supported by grants from the NIH ( HL107653 to A.R.T.; HL132412 , HL075662 , and HL127464 to I.T.; and HL137327 to D.G.T.), the Swedish Science Council , Swedish CIMED grant, the Robert A. Welch Foundation ( E-0004 to J.-A.G.), the Netherlands Organization for Scientific Research (VIDI grant 917.15.350 to M.W.), and the UMCG (Rosalind Franklin Fellowship to M.W.). Research reported in this publication was performed in the CCTI Flow Cytometry Core, which is supported in part by the Office of the Director, NIH under award S10RR027050 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = dec,
day = "26",
doi = "10.1016/j.celrep.2018.11.100",
language = "English (US)",
volume = "25",
pages = "3774--3785.e4",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}