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.
Highlights
Homeostasis of energy metabolism results in a steady-state output of energy available for cell functions, despite the discontinuity of food intake and activities
Differentiated HepaRG cells were chosen since their global gene expression patterns are much closer to liver or primary human hepatocyte cultures than the widely used HepG2 cell line [5]
The numerous side effects associated to novel therapeutics for metabolic disorders based on nuclear receptors (NRs) activation or inhibition highlight the need for understanding their regulatory cross-talks
Summary
Homeostasis of energy metabolism results in a steady-state output of energy available for cell functions, despite the discontinuity of food intake and activities. System analysis of the functional cross-talk between PPARα, LXR and FXR and 310030_156771/1; BD) Novartis (Grant to CC), and FP7 NR-NET (606806; BD). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Liver is a major component of energy homeostasis. Metabolic regulation relies on three main types of control: allosteric, post-translational, and transcriptional. While most metabolic regulations benefit from a coordination of these mechanisms, transcriptional regulation exerts a critical control for keeping each component of the regulatory mechanisms at appropriate operating levels
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