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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [ATAC-Seq]

ABSTRACT: The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying 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 direct repressive functions of LXR also play a key role but are independent of AP-1. We use 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 induction of LXR targets mediating cholesterol efflux.

ORGANISM(S): Mus musculus

PROVIDER: GSE109998 | GEO | 2018/11/17

REPOSITORIES: GEO

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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [RNA-Seq]

Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying 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 direct repressive functions of LXR also play a key role but are independent of AP-1. We use 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 induction of LXR targets mediating cholesterol efflux.

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LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux

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LXR signaling controls homeostatic dendritic cell maturation [scRNAseq]

Project description:Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation.

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Transcription profiling of mouse LXRalpha null, LXRbeta null mutants reveals liver X receptor beta is the dominant LXR subtype in skeletal muscle

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Feedback regulation of cholesterol metabolism by LeXis, a lipid-responsive non-coding RNA

Project description:Abstract: The LXR and SREBP transcription factors are key regulators of cellular and systemic cholesterol homeostasis. The molecular mechanisms that integrate these pathways are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as an unexpected mediator of this effect. LeXis is robustly induced in mouse liver in response to western diet feeding or pharmacologic LXR activation. Expression of LeXis in liver inhibits cholesterol biosynthesis and lowers plasma cholesterol levels. Reciprocally, knockdown of LeXis increases hepatic cholesterol content and raises plasma cholesterol levels. LeXis interacts with the heterogeneous nuclear ribonucleoprotein Raly and regulates its binding to cholesterol biosynthetic gene promoters. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating systemic sterol homeostasis. Global RNA expression from primary hepatocytes treated with or without GW3965 were compared by RNA-Seq.

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Expression data from 12 BPDCN samples, 35 T-ALL samples, and 65 AML samples

Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological. We used transcriptomic analysis to investigate LXR pathway, and cholesterol metabolism in leukemic cells. Malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared to those of acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL), as well as the transcriptomic signature of primary PDC. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of ATP Binding Cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with three signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor IL-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with an increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.

2017-02-10 | GSE89565 | GEO

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRM-NM-1 and LXRM-NM-2 subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRM-NM-1 and LXRM-NM-2 knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRM-NM-1 KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRM-NM-2 KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRM-NM-1 KO mice, but not LXRM-NM-2 KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRM-NM-2 in skeletal muscle. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRa and LXRb knockout (KO) mice were established. Sixteen samples were examined. Half the samples were treated with the unselective LXR agonist T0901317.

2010-03-30 | E-GEOD-13192 | biostudies-arrayexpress

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