System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells
| Autor: | Michaël Baruchet, Aurélien Naldi, Cristina Casals-Casas, Béatrice Desvergne, Sylvain Pradervand, Leonore Wigger, Khanh B. Trang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Benzylamines Systems Analysis Cellular differentiation Gene Expression Receptors Cytoplasmic and Nuclear Cell Cycle Proteins Biochemistry Benzoates 0302 clinical medicine Cell Signaling Animal Cells Medicine and Health Sciences Cell Cycle and Cell Division Promoter Regions Genetic Receptor Liver X Receptors Regulation of gene expression Hepatocyte differentiation 0303 health sciences Multidisciplinary Chemistry Cell Cycle Cell Differentiation Cell cycle Orphan Nuclear Receptors Cell biology Butyrates medicine.anatomical_structure Liver Cellular Crosstalk Cell Processes 030220 oncology & carcinogenesis Hepatocyte Medicine Metabolic Pathways Cellular Types Anatomy Research Article Signal Transduction Agonist medicine.drug_class Science Cell Cycle/genetics Cell Cycle/physiology Cell Cycle Proteins/physiology Cell Differentiation/physiology Cell Line Cell Proliferation/physiology Gene Expression/genetics Gene Expression Regulation/genetics Hepatocytes/metabolism Humans Isoxazoles Liver/pathology Liver X Receptors/immunology Liver X Receptors/metabolism Orphan Nuclear Receptors/metabolism PPAR alpha/immunology PPAR alpha/metabolism Phenylurea Compounds Promoter Regions Genetic/genetics Receptor Cross-Talk/physiology Receptors Cytoplasmic and Nuclear/immunology Receptors Cytoplasmic and Nuclear/metabolism Context (language use) Polyploidy 03 medical and health sciences Genetics medicine Gene Regulation PPAR alpha Liver X receptor Cell Proliferation 030304 developmental biology Biology and Life Sciences Cell Biology Receptor Cross-Talk Tetraploidy Metabolism 030104 developmental biology Gene Expression Regulation Nuclear receptor Hepatocytes Departures from Diploidy Developmental Biology |
| Zdroj: | PLoS ONE PloS one, vol. 14, no. 8, pp. e0220894 PLoS ONE, Vol 14, Iss 8, p e0220894 (2019) |
| DOI: | 10.1101/514976 |
| Popis: | Transcriptional regulations exert a critical control of metabolic homeostasis. In particular, the nuclear receptors (NRs) are involved in regulating numerous pathways of the intermediate metabolism. The purpose of the present study was to explore in liver cells the interconnectedness between three of them, LXR, FXR, and PPARα, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its best 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). Our work revealed that, contrary to our expectations, NR specificity is largely present at the level of target genes, with a smaller than expected overlap of the set of genes targeted by the different NRs. It also highlighted the much broader activity of the synthetic FXR ligand compared to CDCA. More importantly, our results revealed that activation of FXR has a pro-proliferative effect and decreases polyploidy of hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and a higher polyploidism. Conclusion: these results highlight the importance of analyzing the different NR activities in a context allowing a direct confrontation of each receptor outcome, and reveals the opposite role of FXR and LXR in hepatocyte cells division and maturation. |
| Databáze: | OpenAIRE |
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