LXR/RXR complex binds to a liver X receptor response element (LXRE) in the regulatory region of target genes. The LXR receptor is activated by oxysterol ligands and forms a heterodimer with RXR. Affymetrix microarray data and Northern blot assays demonstrated that phospholipid transfer protein (PL222222222216) was induced 6-fold when either murine or human macrophages were incubated in the presence of ligands for the liver X receptor (LXR) and the retinoid X receptor. Here we characterize a novel LXR target gene, the lipopolysaccharide binding pro-tein (LBP) gene. The characterization of LXR target genes in the macrophage, as well as in liver and intestine, and the function of these target genes in RCT and … the transcription of target genes by binding to specific sites in the promoter regions of these genes, called response elements. A, THP1 macrophages were treated for 6 h with 1 μmol/L GW3965 or vehicle control in the presence of 10 μg/mL cycloheximide. Steroids, 118:119-127, 21 Dec 2016 Cited by: 2 articles | PMID: 28011133 Synthesis, in silico and in vitro evaluations. Surprisingly, the genes involved in PUFA metabolism were not induced or even slightly inhibited in the liver of LXR-agonist treated mice (Figure X in the online-only Data Supplement). In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. the promoter region of target genes. 2003. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. Enolase is a new target of liver X receptors. J. Lipid Res. Studies using genetic knockouts and synthetic LXR agonists identified the genes encoding the ATP‐binding cassette transporters, ABCA1 and ABCG1, as well as the gene encoding apolipoprotein E (APOE) as direct LXR target genes with one or more LXR‐binding sites in the promoters and transcriptional enhancers associated with all 3 genes [21-23]. Viktorsson EÖ, Gabrielsen M, Kumarachandran N, Sylte I, Rongved P, Åstrand OA, Kase ET. Endonuclease–exonuclease–phosphatase family domain containing 1 (EEPD1) is a direct liver X receptors (LXR) target gene in human and mouse macrophages. Characterization of new LXR target genes and consequences on lipid metabolism and atherosclerosis . A Analysis of LXR peak versus T09 target gene pairs by relating the log 2 FC of target genes with the similarity of the DR4-type REs within the closest LXR peak (± 100 kb limit). Download with Google Download with Facebook. Remarkably, LXR target genes are activated in Kupffer cells in response to DMHCA, in contrast to liver as a whole. motifs, termed LXR response elements (LXREs), in the regu-latory regions of target genes (1–4). Regulation of liver X receptor target genes by 22-functionalized oxysterols. Gene expression profiling revealed that the elevated production of 24S‐OHC did not result in the anticipated activation of LXR target genes in the brain or liver. The Nuclear Receptor Rev-erb Is a Liver X Receptor (LXR) Target Gene Driving a Negative Feedback Loop on Select LXR-Induced Pathways in Human Macrophages. Members of the ARL family … In contrast to other known LXR target genes, SPα is not known to be involved in lipid metabolism. The nuclear receptor Rev-erbalpha is a liver X receptor (LXR) target gene driving a negative feedback loop on select LXR-induced pathways in human macrophages Mol Endocrinol. The natural and synthetic LXR agonists induce the transcriptional activity of LXR target genes, thus attenuate the imbalance of cholesterol metabolism and overactivation of microglia and astrocytes in inflammation and are widely used in a variety … Surprisingly, the ability of LXRs to control LBP expression is cell-type specifi c, occurring in mac-rophages but not liver. Data suggest that liver X receptor (LXR)/B-lymphocyte stimulator (BLyS) pathway may serve as a target for the treatment of rheumatoid arthritis (RA). The nuclear receptors liver X receptor (LXR)α and LXRβ are sensors of cholesterol metabolism and lipid biosynthesis. Low expression of LXR target genes has been associated with poor clinical outcome and resistance to immunotherapy. LXR target genes with DR4-type REs. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. 2008 Aug;22(8):1797-811. doi: 10.1210/me.2007-0439. Data show that menin, encoded by the MEN1 gene, inhibits the transcriptional activity of nuclear receptor liver X receptor alpha (LXRalpha). PDF. They have recently been found to be regulators of inflammatory cytokines, suppressors of hepatic glucose production, and involved in different cell-signaling pathways. On the other hand, the LXR target genes fatty acid synthase (Fasn) and stearoyl-Coenzyme A desaturase 2 (Scd2) were not changed upon LXR activation between the two genotypes (Figure 4A), proposing that the deletion of NCOR1 in macrophage primarily affects the function of PPARγ. In concert, these findings suggest a molecular basis for dissociation of LXR functions in macrophages and hepatocytes that would enable retention of antiatherogenic properties without promoting hypertriglyceridemia. LXR acts as a ligand-activated tran-scription factor, and the initiation or blockade of tar-get gene transcription is determined by the presence of coactivator or corepressor complexes4). Coralie Fontaine. SREBP and LXR target genes identified by micr oarray anal-ysis in liver of cholester ol-fed mice. ADP riboyslation factor-like 7 (ARL7) was identified as a novel target gene. Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES. Download Free PDF. The role of LXR target genes in cholesterol metabolism and inflammatory signaling. In peripheral cells such as macrophages ABCA1 and ABCG1 function as cholesterol transporters that mediate the transfer of Figure 5 ApoE/LRP8 Signaling Regulates MDSC Survival Downstream of LXR Agonism. As cholesterol-sensing nuclear receptors, LXRs promote cholesterol efflux via regulation of CPY7A1, ABCA1, ABCG1, ABCG4, ABCG5 apolipoproteins, lipoprotein remodeling enzymes and lipogenesis. After heterodimerization LXR initiates transcription of target genes by binding to the LXR response element. Rather, the SPα protein is a member of the family of SRCR proteins that has been shown to be important for macrophage/Kupffer cell immune function. The “ideal” LXRE sequence is a direct repeat‐4 (DR‐4) DNA fragment consisting of two AGGTCA hexameric motifs separated by 4‐nucleotide spacer. LXR/RXR is involved in the regulation of lipid metabolism, … Abstract. It is well recognized that both FXR and LXR partner with RXR, but bind to distinct DNA recognition motifs and regulate different sets of metabolic genes. Les récepteurs nucléaires LXRα et LXRβ sont activés par la fixation de dérivés oxygénés du cholestérol. Free PDF. To further increase our understanding of the role of LXR in metabolism and inflammation, we employed this transgenic model to identify new LXR target genes. Epub 2008 May 29. LXR forms When cells were treated with 1 μ m TO901317 plus 1 μ m 9- cis -retinoic acid, there was a further reduction in Aβ secretion to 20% of control ( Fig. DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXREs. For each peak, the gene with the smallest expression P-value in … By Alexis Varin. Other well-characterized members of this family include scavenger receptor A, MARCO, and CD163. As expected, LXR treatment resulted in liver steatosis and in the induction of LXR target genes such as Scd1 and Srebp1 (Figure X in the online-only Data Supplement). 1 B ). Similar induction patterns of LXR target genes in response to agonists were observed in 2 additional primary RPE cell lines (from a 15- and 60-year-old). LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. LXR target genes with one or more LXR-binding sites in the promoters and transcriptional enhancers associ-ated with all 3 genes [21–23]. Supplementar y key words. [Key Words: RXR; LXR; orphan receptor; retinoid receptors; 9-cis retinoic acid; methoprene acid] Received February 1, 1995; revised version accepted March 17, 1995. Genes. Liver X Receptor (LXR) modulators have shown potential as drugs since they target genes affecting metabolism and fatty acid synthesis. genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. 44: 2109–2119. Conclusion. LXR acts in a heterodimeric complex with retinoid X receptor (RXR), and the response of genes to LXR activators is increased in the presence of RXR activators, such as 9-cis-retinoic acid . The ideal LXRE sequence is a direct repeat-4 DNA fragment consist-ing of two AGGTCA hexameric half-sites separated by four nucleotides. These findings reveal that the LXR transcriptional target gene Apoe mediates LXR-dependent MDSC depletion. Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity. However, the LXRE in specific target genes may differ from this ideal sequence. Whereas LXR is ex-pressed in most tissues, LXR is abundantly expressed in a more restricted set of tissues including the liver, kidney, spleen, intestine, and in macrophages (1–4). Molecular Endocrinology, 2008. or. Together, FXR and LXR maintain bile acid and cholesterol homeostasis by translating hormonal, metabolic and nutritional signals into changes in target gene expression (6,33-35). 14 target genes of the LXR transcription factor predicted using known transcription factor binding site motifs from the MotifMap Predicted Transcription Factor Targets dataset.