LXR activation in RAW264.7 mouse macrophages expressing LXRalpha.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE17088 | GEO | 2009/08/01
SECONDARY ACCESSION(S): PRJNA117829
REPOSITORIES: GEO
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Project description:To identify novel LXR target genes, we conducted transcriptional profiling studies using RAW264.7 cells ectopically expressing LXRalpha Total RNA was isolated from RAW264.7 macrophages ectopically expressing LXRalpha as described in Venkateswaran et al. (2000); PNAS 97, 12097-12102. Cells were cultured with DMSO or GW3965 (1 μM) and LG268 (100 nM). Transcriptional profiling was performed at the UCLA microarray core facility using murine Affymetrix 430 2.0 microarrays.
2009-08-01 | E-GEOD-17088 | biostudies-arrayexpress
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 LXRalpha (NR1H3) and LXRbeta (NR1H2) 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), LXRalpha and LXRbeta 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 LXRalpha KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRbeta 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 LXRalpha KO mice, but not LXRbeta KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRbeta in skeletal muscle.
2009-10-01 | E-MTAB-61 | biostudies-arrayexpress
Project description:Bone marrow derived macrophages were isolated from C57BL/6J (LXR positive) and LXRalpha +LXRbeta double knockout mice (DKO) that had been treated with vehicle, Kado2-lipid A (KLA, and inflammatory stimulus), acetylated LDL (AcLDL, a mimic of pro-atherogenic lipoprotein particles) and GW3965 (GW, a synthetic LXR agonist) for 17 hours. Following treatment RNA was isolated and RNA-Seq was performed.
2018-08-17 | GSE118656 | GEO
Project description:LXR activation in RAW264.7 mouse macrophages expressing LXRalpha.
| PRJNA117829 | ENA
Project description:To investigate how LXR activation potentiates expression of Th2 cytokine-dependent genes in primary human macrophages, we pulsed macrophages with synthetic LXR ligand T0901317 then polarized cells to alternatively activated macrophages with IL-4 or IL-13.
2021-04-14 | GSE158022 | GEO
Project description:Damaging mutations in LXRalpha are associated with hepatotoxicity. We generated mice homozygous for a dominant-negative mutation in LXRalpha (LXRalpha-W441R) and discovered they develop severe liver injury when fed a Western diet, though knockout mice develop little to no liver injury. To examine this in further detail, we performed Bulk RNA-seq of livers from LXRalpha knockout and LXRalpha p.W441R knockin mice after 8 weeks of western diet (TD.88137).
2024-07-31 | GSE273156 | GEO
Project description:Background & Aims: Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. Methods: We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah-/-) mice, which led to highly penetrant HCC. We treated mice with vehicle or sorafenib, then determined the genetic drivers of each tumor from the library. Liver X Receptor alpha (LXRalpha) emerged as a potential target. To examine LXRalpha agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXRalpha agonist drugs to HCC cell lines. To elucidate the mechanism of tumor death, we performed transcriptomic analysis. Results: Fah-/- mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXRalpha, suggesting that LXRalpha activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. Combination treatment using sorafenib and LXR agonist drugs in multiple HCC cell lines led to enhanced cell death as compared to monotherapy, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Conclusions: We have completed a novel drug resistance screen in vivo, and identified that LXR agonism potentiates the efficacy of sorafenib in treating HCC.
2020-05-29 | GSE151412 | GEO
Project description:Efferocytosis is critical for tissue homeostasis, as its deregulation is associated with several autoimmune pathologies. While engulfing apoptotic cells, phagocytes activate transcription factors, such as peroxisome proliferator-activated receptors (PPAR) or liver X receptors (LXR) that orchestrate metabolic, phagocytic, and inflammatory responses towards the ingested material. Coordination of these transcription factors in efferocytotic human macrophages (MF) is not fully understood. In this study, we evaluated the transcriptional profile of MF following the uptake of apoptotic Jurkat T cells using RNA-seq analysis. Results indicated upregulation of PPAR and LXR pathways but downregulation of sterol regulatory element-binding proteins (SREBP) target genes. Pharmacological inhibition and RNA interference pointed to LXR and PPARdelta as relevant transcriptional regulators, while PPARdelta did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPARdelta activation also demanded an active lysosomal phospholipase A2 (PLA2G15). Pharmacological interference with LXR signaling attenuated ABCA1-dependent cholesterol efflux from efferocytotic MF, but suppression of inflammatory responses following efferocytosis occurred independently of LXR and PPARdelta. These data provide mechanistic details on LXR and PPARdelta activation in efferocytotic human MF.
2021-05-26 | GSE169160 | GEO
Project description:The Liver X Receptors (LXRs) play important roles in multiple metabolic pathways, including fatty acid, cholesterol, carbohydrate and energy metabolism. To expand the knowledge of the functions of LXR signaling during embryonic development, we performed a whole-genome microarray analysis of Lxr target genes in zebrafish larvae treated with either one of the synthetic LXR ligands T0901317 or GW3965. Assessment of the biological processes enriched by differentially expressed genes revealed a prime role for Lxr in regulating lipid metabolic processes, similarly to the function of LXR in mammals. In addition, exposure to the Lxr ligands induced changes in expression of genes in the neural retina and lens of the zebrafish eye, including the photoreceptor guanylate cyclase activators and lens gamma crystallins, suggesting a potential novel role for Lxr in modulating the transcription of genes associated with visual function in zebrafish. The regulation of expression of metabolic genes was phenotypically reflected in an increased absorption of yolk in the zebrafish larvae, and changes in the expression of genes involved in visual perception were associated with morphological alterations in the retina and lens of the developing zebrafish eye. The regulation of expression of both lipid metabolic and eye specific genes was sustained in 1 month old fish. The transcriptional networks demonstrated several conserved effects of LXR activation between zebrafish and mammals, and also identified potential novel functions of Lxr, supporting zebrafish as a promising model for investigating the role of Lxr during development.
2016-03-07 | GSE59031 | GEO
Project description:The LXR proteins, LXRα and LXRβ, are transcription factors that belong to the nuclear receptor superfamily. LXRs are activated by oxysterols and control the transcription of genes involved in the regulation of cholesterol and fatty acid metabolism. They also mediate several aspects of macrophage biology, including inflammatory responses, cell survival in response to infection and phagocytosis of apoptotic cells. LXRs share a high degree of sequence homology and most of their functions are believed to be performed similarly by LXRα and LXRβ. However, the individual, transcriptional roles of each LXR isoform have not been characterized in detail, in part due to the lack of specific experimental tools that can discriminate between LXRα and LXRβ actions. To identify common and differential transcriptional functions of LXR nuclear receptors in macrophages, we developed a cellular model of stable expression of FLAG-tagged LXRα or LXRβ in LXR-null immortalized murine bone marrow-derived macrophages (parental line published Elife. 2015 Jul 14;4:e08009. doi: 10.7554/eLife.08009). To take a deeper insight into the epigenomic features of LXR nuclear receptors, we performed chromatin immunoprecipitation coupled to next-generation sequencing (ChIP-seq) to identify genome-wide binding locations of LXRα and LXRβ in the presence of a synthetic agonist (GW3965, 1uM). Additionally, we identified genome-wide DNA locations of acetylation mark on lysine 27 of histone H3 (H3K27ac), upon LXR agonist (GW3965, 1uM) and antagonist (GW2033, 1uM) treatment. Collectively, these studies will increase our understanding of common and differential genomic actions of LXRα and LXRβ in cultured murine macrophages.
2017-10-19 | GSE104027 | GEO