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Development of gene expression signatures in the liver cancer cells with FXR overexpression and FXR activation

ABSTRACT: To investigate the role of nuclear receptor FXR during hepatocarcinogenesis, HepG2 cels and SK-Hep-1 cells were transfected with lentiviral mediated FXR overexpressive vector or the negative control. After the cells were treated with FXR agonist GW4064 2uM for 24 h, and total RNA were isolated for detection of gene expression .

ORGANISM(S): Homo sapiens

PROVIDER: GSE149111 | GEO | 2020/09/10

REPOSITORIES: GEO

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FXR protects cisplatin-induced AKI via transcriptional regulation of ferroptosis.

Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.

2022-07-06 | GSE193860 | GEO

System Analysis of The Functional Cross-Talk Between PPARα, LXR and FXR in HepaRG Liver Cells

Project description:The purpose of the present study was to explore in liver cells the connectivity that operates between three nuclear receptors in the liver, LXR, FXR, and PPARa, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its proximity to human primary hepatocytes. Global gene expression of differentiated HepaRG cells was assessed after 4 hours and 24 hours of exposure to GW3965 (LXR agonist), GW7647 (PPARα agonist), and GW4064 and CDCA (FXR synthetic and natural agonist, respectively).

2019-06-27 | GSE124053 | GEO

A dysregulated Acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

Project description:Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and -defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated Acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. FXR-WT or the FXR-K217Q mutant was expressed in lean mice and FXR-WT or the FXR-K217R mutant was expressed in obese mice by adenoviral infection. One week after infection, mice were treated with GW4064 (30 mg/kg in corn oil) overnight before sacrifice and hepatic expression was analyzed by Illumina microarray.

2014-10-17 | E-GEOD-62414 | biostudies-arrayexpress

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR

Project description:Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD) and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

2023-10-16 | GSE229049 | GEO

Genome wide binding and transcriptome analysis of human FXR in primary human hepatocytes [HTS]

Project description:We report the genome-wide profiling of FXR binding by ChIP-seq from GW4064 or DMSO treated primary human hepatocytes. We reported altered RNA expression profiles in primary human hepatocypes upon GW4064 treatment compared to DMSO control by RNA-seq. We also reported the altered RNA expression profiles in livers from WT C57BL/6J mice upon GW4064 treatment compared to vehicle control. Primary human hepatocytes were treated with 5uM GW4064 or DMSO control, 1 hour later, cells were fixed and collected for chromatin isolation. 24 hours post treatment, cells were isolated for RNA isolation. This submission represents HTS component of study.

2014-07-24 | E-GEOD-57227 | biostudies-arrayexpress

Genome wide binding and transcriptome analysis of human FXR in primary human hepatocytes [HTS]

2014-07-24 | GSE57227 | GEO

Gene expression in BMDM treated with GW4064

Project description:We have employed whole genome microarray expression profiling with the samplaes prepared by treating BMDM with GW4064, an fxr agonist. Some genes upregulated in GW4064 treated sample were used for qPCR to confirm the change of expression level.

2022-11-04 | GSE216995 | GEO

Transcription profiling of liver from farnesoid X receptor knockout mice

Project description:Expression profiling of whole body (WB) FXR knockout (KO) mice (FXR WB KO), liver-specific FXR KO mice (AFXR Cre+) and enterocyte specific FXR KO mice (VFXR Cre+) on a C57BL/6J genetic background Whole body (WB) FXR knockout (KO) mice (FXR WB KO), liver-specific FXR KO mice (AFXR Cre+) and enterocyte specific FXR KO mice (VFXR Cre+) on a C57BL/6J genetic background were bred and maintained in the laboratory animal research facility at the University of Kansas Medical Center in rooms under a 12-hour light-dark cycle. All experiments used 10-16 week-old male mice. FXR was activated by treatment with the FXR synthetic agonist, GW4064, at 150 mg/kg. GW4064 or vehicle was administered by oral gavage at 6 p.m., followed by a second administration at 8 a.m. the next morning. Two hours later, the liver was harvested.

2014-01-31 | E-GEOD-54557 | biostudies-arrayexpress

Effect of GW4064 on primary cultured mouse kidney proximal tubule cells

Project description:Global gene expression in the primary cultured mouse kidney proximal tubule cells treated either DMSO or 1uM GW4064 (a FXR agonist) was compared. Results provide insight into mechanisms underlying effects of FXR activation on gene expression in mouse kidney proximal tubule cells. Male C57/BJ mice aged 6 weeks were sacrificed under anesthesia and kidney proximal tubule cells were cultured until confluent. Cells were treated with either GW4064 (1uM) or equal amount of DMSO and incubated for 24 hours. 4 total RNA samples per group were analyzed and gene expression was compared between the groups.

2015-06-26 | E-GEOD-70296 | biostudies-arrayexpress

Effect of GW4064 on primary cultured mouse kidney proximal tubule cells

Project description:Global gene expression in primary cultured mouse kidney proximal tubule cells treated with either DMSO or 1uM GW4064 (an FXR agonist) was compared. Results provide insight into mechanisms underlying effects of FXR activation on gene expression in mouse kidney proximal tubule cells.

2015-06-26 | GSE70296 | GEO

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