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

JOURNAL OF HEPATOLOGY

卷:69

Article

Ploton, Maheul¹  Mazuy, Claire¹  Gheeraert, Celine¹  Dubois, Vanessa¹  Berthier, Alexandre¹  Dubois-Chevalier, Julie¹  Marechal, Xavier¹  Bantubungi, Kadiombo¹  Diemer, Helene²  Cianferani, Sarah²  Strub, Jean-Marc²  Helleboid-Chapman, Audrey¹  Eeckhoute, Jerome¹  Staels, Bart¹  Lefebvre, Philippe¹ 

[1] Univ Lille, CHU Lille, INSERM, Inst Pasteur Lille,U1011,EGID, F-59000 Lille, France

[2] Univ Strasbourg, CNRS UMR7178, IPHC, Lab Spectrometrie Masse BioOrgan, F-67087 Strasbourg, France

关键词: Liver;    Gluconeogenesis;    Glucagon;    PKA;    Transcription;    Nuclear receptor;    Bile acid;    FXR;    FOXA2;   

DOI  :  10.1016/j.jhep.2018.06.022

来源: Elsevier

【 摘 要 】

Background & Aims: Embedded into a complex signaling network that coordinates glucose uptake, usage and production, the nuclear bile acid receptor FXR is expressed in several glucose-processing organs including the liver. Hepatic gluconeogenesis is controlled through allosteric regulation of gluconeogenic enzymes and by glucagon/cAMP-dependent transcriptional regulatory pathways. We aimed to elucidate the role of FXR in the regulation of fasting hepatic gluconeogenesis. Methods: The role of FXR in hepatic gluconeogenesis was assessed in vivo and in mouse primary hepatocytes. Gene expression patterns in response to glucagon and FXR agonists were characterized by quantitative reverse transcription PCR and microarray analysis. FXR phosphorylation by protein kinase A was determined by mass spectrometry. The interaction of FOXA2 with FXR was identified by cistromic approaches and in vitro protein-protein interaction assays. The functional impact of the crosstalk between FXR, the PKA and FOXA2 signaling pathways was assessed by site-directed mutagenesis, transactivation assays and restoration of FXR expression in FXR-deficient hepatocytes in which gene expression and glucose production were assessed. Results: FXR positively regulates hepatic glucose production through two regulatory arms, the first one involving protein kinase A-mediated phosphorylation of FXR, which allowed for the synergistic activation of gluconeogenic genes by glucagon, agonist-activated FXR and CREB. The second arm involves the inhibition of FXR's ability to induce the anti-gluconeogenic nuclear receptor SHP by the glucagon-activated FOXA2 transcription factor, which physically interacts with FXR. Additionally, knockdown of Foxa2 did not alter glucagon-induced and FXR agonist enhanced expression of gluconeogenic genes, suggesting that the PKA and FOXA2 pathways regulate distinct subsets of FXR responsive genes. Conclusions: Thus, hepatic glucose production is regulated during physiological fasting by FXR, which integrates the glucagon/cAMP signal and the FOXA2 signal, by being post-translationally modified, and by engaging in protein-protein interactions, respectively. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

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