The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis
Author(s): ,
Philippe Lefebvre
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
Corresponding authors. Addresses: INSERM UMR1011-Institut Pasteur de Lille, 1 rue du Pr Calmette, BP245, 59019 Lille, France (B. Staels), or INSERM UMR1011-Bâtiment J&K; Faculté de Médecine de Lille, Boulevard du Pr Leclerc, 59045 Lille cedex, France (
,
Bart Staels
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
Corresponding authors. Addresses: INSERM UMR1011-Institut Pasteur de Lille, 1 rue du Pr Calmette, BP245, 59019 Lille, France (B. Staels), or INSERM UMR1011-Bâtiment J&K; Faculté de Médecine de Lille, Boulevard du Pr Leclerc, 59045 Lille cedex, France (
,
Jérôme Eeckhoute
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Audrey Helleboid-Chapman
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Jean-Marc Strub
Affiliations:
Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ Strasbourg, IPHC, F-67087 Strasbourg, France
,
Sarah Cianférani
Affiliations:
Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ Strasbourg, IPHC, F-67087 Strasbourg, France
,
Hélène Diemer
Affiliations:
Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ Strasbourg, IPHC, F-67087 Strasbourg, France
,
Kadiombo Bantubungi
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Xavier Maréchal
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Julie Dubois-Chevalier
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Alexandre Berthier
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Vanessa Dubois
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Céline Gheeraert
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
,
Claire Mazuy
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
Maheul Ploton
Affiliations:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 – EGID, F-59000 Lille, France
EASL LiverTree™. LEFEBVRE P. Nov 1, 2018; 234544
Philippe LEFEBVRE
Philippe LEFEBVRE

Access to this content is an EASL members and LiverTree™ Privileged Users benefit.

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Graphical abstract

Graphical abstract

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.

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.

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.

Keyword(s)
Liver, Gluconeogenesis, Glucagon, PKA, Transcription, Nuclear receptor, Bile acid, FXR, FOXA2
[1]. L. Rui - Energy metabolism in the liver
[2]. J.E. Gerich - Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications
[3]. M. Soty - Gut-brain glucose signaling in energy homeostasis
[4]. K. Sharabi - Molecular pathophysiology of hepatic glucose production
[5]. P. Karagianni - Transcription factor networks regulating hepatic fatty acid metabolism
[6]. M.H. Oosterveer - Hepatic glucose sensing and integrative pathways in the liver
[7]. H.V. Lin - Hormonal regulation of hepatic glucose production in health and disease
[8]. S.J. Pilkis - Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis
[9]. M.R. El-Maghrabi - The rat fructose-1,6-bisphosphatase gene. Structure and regulation of expression
[10]. J.C. Hutton - Glucose-6-phosphatase catalytic subunit gene family
[11]. N. Shen - The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis
[12]. A.K. Rines - Targeting hepatic glucose metabolism in the treatment of type 2 diabetes
[13]. C. Mazuy - Nuclear bile acid signaling through the farnesoid X receptor
[14]. J. Prawitt - Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity
[15]. M.S. Trabelsi - Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells
[16]. D. Duran-Sandoval - The Farnesoid X Receptor Modulates Hepatic Carbohydrate Metabolism during the Fasting-Refeeding Transition
[17]. S. Caron - Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes
[18]. Y. Zhang - Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice
[19]. S. Cipriani - FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats
[20]. K. Ma - Farnesoid X receptor is essential for normal glucose homeostasis
[21]. L. Jin - The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism
[22]. Y. Ma - Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance
[23]. M.J. Park - Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPalpha
[24]. K. Yamagata - Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1
[25]. B. Cariou - FXR-deficiency confers increased susceptibility to torpor
[26]. B. Cariou - Transient impairment of the adaptive response to fasting in FXR-deficient mice
[27]. B. Cariou - The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice
[28]. B. Renga - Glucocorticoid receptor mediates the gluconeogenic activity of the farnesoid X receptor in the fasting condition
[29]. G. Porez - The hepatic orosomucoid/alpha1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR
[30]. C.J. Sinai - Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis
[31]. W. Berrabah - Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR)
[32]. F. Lien - Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk
[33]. R. Gineste - Phosphorylation of farnesoid X receptor by protein kinase C promotes its transcriptional activity
[34]. X.J. Fang - Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A
[35]. A.M. Thomas - Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine
[36]. L.J. Everett - Integrative genomic analysis of CREB defines a critical role for transcription factor networks in mediating the fed/fasted switch in liver
[38]. B.M. Forman - Identification of a nuclear receptor that is activated by farnesol metabolites
[39]. J.J. Howell - Nuclear export-independent inhibition of Foxa2 by insulin
[40]. C. Wolfrum - Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization
[41]. I.M. Bochkis - Foxa2-dependent hepatic gene regulatory networks depend on physiological state
[42]. R.E. Soccio - Species-specific strategies underlying conserved functions of metabolic transcription factors
[43]. T. Sekiya - Nucleosome-binding affinity as a primary determinant of the nuclear mobility of the pioneer transcription factor FoxA
[44]. O. Chavez-Talavera - Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease
[45]. K.R. Stayrook - Regulation of carbohydrate metabolism by the farnesoid X receptor
[46]. M. Watanabe - Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure
[47]. J.K. Kemper - FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states
[48]. J.L. Garcia-Rodriguez - SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling
[49]. J. Wang - Nuclear proteomics uncovers diurnal regulatory landscapes in mouse liver
[50]. M.S. Robles - Phosphorylation is a central mechanism for circadian control of metabolism and physiology
[51]. J. Dubois-Chevalier - The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions
[52]. P. Lefebvre - Role of bile acids and bile acid receptors in metabolic regulation
[53]. Y. Zhang - Role of nuclear receptor SHP in metabolism and cancer
[54]. J.Y. Kim - Orphan nuclear receptor small heterodimer partner represses hepatocyte nuclear factor 3/Foxa transactivation via inhibition of its DNA binding
[55]. F. von Meyenn - Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism
[56]. C. Wolfrum - Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes
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