The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis

Maheul Ploton 1 Claire Mazuy 1 Celine Gheeraert 1 Vanessa Dubois 1 Alexandre Berthier 1 Julie Dubois 1 Xavier Marechal 1 Kadiombo Bantubungi 1 Hélène Diemer 2 Sarah Cianférani 2 Jean-Marc Strub 2 Audrey Helleboid-Chapman 1 Jérôme Eeckhoute 1 Bart Staels 1, * Philippe Lefebvre 1, *
* Corresponding author
1 EGID - Récepteurs nucléaires, maladies cardiovasculaires et diabète
2 IPHC - Institut Pluridisciplinaire Hubert Curien
Abstract : The nuclear bile acid receptor FXR is a PKA-and FOXA2-sensitive activator of fasting hepatic gluconeogenesis Graphical abstract Authors Gluconeogenesis control by FXR Glucagon cAMP PKA CREB SHP BAs FXR::FOXA2 FXR S325,357P Gluconeogenesis Glucose Hepatocyte Highlights FXR synergizes with the glucagon signaling pathway to regulate hepatic gluconeogenesis in vivo and in vitro. FXR positively regulates gluconeogenic genes through PKA-catalyzed phosphorylation. The glucagon-regulated transcription factor FOXA2 negatively regulates FXR's ability to activate the expression of the SHP. Lay summary Activation of the nuclear bile acid receptor FXR regulates gene expression networks , controlling lipid, cholesterol and glucose metabolism, which are mostly effective after eating. Whether FXR exerts critical functions during fasting is unknown. The results of this study show that FXR transcriptional activity is regulated by the glucagon/protein kinase A and the FOXA2 signaling pathways, which act on FXR through phosphorylation and protein-protein interactions, respectively, to increase hepatic glucose synthesis.
Keywords : Glucagon Gluconeogenesis FXR FOXA2 Bile acid Liver Nuclear receptor PKA Transcription
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Maheul Ploton, Claire Mazuy, Celine Gheeraert, Vanessa Dubois, Alexandre Berthier, et al.. The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis. Journal of Hepatology, Elsevier, 2018, 69 (5), pp.1099-1109. ⟨10.1016/j.jhep.2018.06.022⟩. ⟨inserm-02108132⟩

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