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.

Details

Serval ID
serval:BIB_3BDAB76BD0D3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
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.
Journal
PloS one
Author(s)
Wigger L., Casals-Casas C., Baruchet M., Trang K.B., Pradervand S., Naldi A., Desvergne B.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2019
Peer-reviewed
Oui
Volume
14
Number
8
Pages
e0220894
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
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 the number of tetraploid (or binucleated) hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and an increase in tetraploidism. 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.
Keywords
Benzoates, Benzylamines, Butyrates, 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, Systems Analysis
Pubmed
Web of science
Open Access
Yes
Create date
16/09/2019 23:02
Last modification date
07/12/2021 7:38
Usage data