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1. The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPARα

Author

Clavreul, Ludivine, Bernard, Lucie, Cotte, Alexia K., Hennuyer, Nathalie, Bourouh, Cyril, Devos, Claire, Helleboid, Audrey, Haas, Joel T., Verrijken, An, Gheeraert, Céline, Derudas, Bruno, Guille, Loïc, Chevalier, Julie, Eeckhoute, Jérôme, Vallez, Emmanuelle, Dorchies, Emilie, Van Gaal, Luc, Lassailly, Guillaume, Francque, Sven, Staels, Bart, and Paumelle, Réjane

Published
2024
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2. Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis

Author

Lalloyer, Fanny, Mogilenko, Denis A., Verrijken, Ann, Haas, Joel T., Lamazière, Antonin, Kouach, Mostafa, Descat, Amandine, Caron, Sandrine, Vallez, Emmanuelle, Derudas, Bruno, Gheeraert, Céline, Baugé, Eric, Despres, Gaëtan, Dirinck, Eveline, Tailleux, Anne, Dombrowicz, David, Van Gaal, Luc, Eeckhoute, Jerôme, Lefebvre, Philippe, Goossens, Jean-François, Francque, Sven, and Staels, Bart

Published
2023
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3. Pharmacological HDAC inhibition impairs pancreatic β-cell function through an epigenome-wide reprogramming

Author

Oger, Frédérik, Moreno, Maeva, Derhourhi, Mehdi, Thiroux, Bryan, Berberian, Lionel, Bourouh, Cyril, Durand, Emmanuelle, Amanzougarene, Souhila, Badreddine, Alaa, Blanc, Etienne, Molendi-Coste, Olivier, Pineau, Laurent, Pasquetti, Gianni, Rolland, Laure, Carney, Charlène, Bornaque, Florine, Courty, Emilie, Gheeraert, Céline, Eeckhoute, Jérôme, Dombrowicz, David, Kerr-Conte, Julie, Pattou, François, Staels, Bart, Froguel, Philippe, Bonnefond, Amélie, and Annicotte, Jean-Sébastien

Published
2023
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4. Genetic evidence of causal relation between intestinal glucose absorption and early postprandial glucose response: a Mendelian randomization study

Author

Peschard, Simon, primary, Raverdy, Violeta, primary, Bauvin, Pierre, primary, Goutchtat, Rebecca, primary, Touche, Veronique, primary, Derudas, Bruno, primary, Gheeraert, Celine, primary, Dubois-Chevalier, Julie, primary, Caiazzo, Robert, primary, Baud, Gregory, primary, Marciniak, Camille, primary, Verkindt, Helene, primary, Oukhouya Daoud, Naima, primary, W Le Roux, Carel, primary, Lefebvre, Philippe, primary, Staels, Bart, primary, Lestavel, Sophie, primary, and Pattou, François, primary

Published
2024
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5. Genetic Evidence of Causal Relation Between Intestinal Glucose Absorption and Early Postprandial Glucose Response: A Mendelian Randomization Study.

Author

Peschard, Simon, Raverdy, Violeta, Bauvin, Pierre, Goutchtat, Rebecca, Touche, Veronique, Derudas, Bruno, Gheeraert, Celine, Dubois-Chevalier, Julie, Caiazzo, Robert, Baud, Gregory, Marciniak, Camille, Verkindt, Helene, Oukhouya Daoud, Naima, Le Roux, Carel W., Lefebvre, Philippe, Staels, Bart, Lestavel, Sophie, and Pattou, François

Subjects
HYPERGLYCEMIA, INTESTINAL absorption, GLUCOSE, GENE expression, GLUCOSE tolerance tests, TYPE 2 diabetes
Abstract

The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium–glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of −0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of −0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of −0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes Article Highlights: Loss-of-function variant of SGLT1 is associated with reduced intestinal SGLT1 expression and early postload glucose response. Mendelian randomization supports the causal relationship between intestinal glucose absorption and postprandial glucose. Modulating intestinal SGLT1 expression/function is a promising avenue for the prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex

Author

Berthier, Alexandre, Vinod, Manjula, Porez, Geoffrey, Steenackers, Agata, Alexandre, Jérémy, Yamakawa, Nao, Gheeraert, Céline, Ploton, Maheul, Maréchal, Xavier, Dubois-Chevalier, Julie, Hovasse, Agnès, Schaeffer-Reiss, Christine, Cianférani, Sarah, Rolando, Christian, Bray, Fabrice, Duez, Hélène, Eeckhoute, Jérôme, Lefebvre, Tony, Staels, Bart, and Lefebvre, Philippe

Published
2018

7. Nucleotide-binding oligomerization domain 1 (NOD1) modulates liver ischemia reperfusion through the expression adhesion molecules

Author

Lassailly, Guillaume, Bou Saleh, Mohamed, Leleu-Chavain, Natascha, Ningarhari, Massih, Gantier, Emilie, Carpentier, Rodolphe, Artru, Florent, Gnemmi, Viviane, Bertin, Benjamin, Maboudou, Patrice, Betbeder, Didier, Gheeraert, Céline, Maggiotto, François, Dharancy, Sébastien, Mathurin, Philippe, Louvet, Alexandre, and Dubuquoy, Laurent

Published
2019
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8. Hepatic PPARα is critical in the metabolic adaptation to sepsis

Author

Paumelle, Réjane, Haas, Joel T., Hennuyer, Nathalie, Baugé, Eric, Deleye, Yann, Mesotten, Dieter, Langouche, Lies, Vanhoutte, Jonathan, Cudejko, Céline, Wouters, Kristiaan, Hannou, Sarah Anissa, Legry, Vanessa, Lancel, Steve, Lalloyer, Fanny, Polizzi, Arnaud, Smati, Sarra, Gourdy, Pierre, Vallez, Emmanuelle, Bouchaert, Emmanuel, Derudas, Bruno, Dehondt, Hélène, Gheeraert, Céline, Fleury, Sébastien, Tailleux, Anne, Montagner, Alexandra, Wahli, Walter, Van Den Berghe, Greet, Guillou, Hervé, Dombrowicz, David, and Staels, Bart

Published
2019
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10. Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study

Author

Montaigne, David, Marechal, Xavier, Modine, Thomas, Coisne, Augustin, Mouton, Stéphanie, Fayad, Georges, Ninni, Sandro, Klein, Cédric, Ortmans, Staniel, Seunes, Claire, Potelle, Charlotte, Berthier, Alexandre, Gheeraert, Celine, Piveteau, Catherine, Deprez, Rebecca, Eeckhoute, Jérome, Duez, Hélène, Lacroix, Dominique, Deprez, Benoit, Jegou, Bruno, Koussa, Mohamed, Edme, Jean-Louis, Lefebvre, Philippe, and Staels, Bart

Published
2018
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11. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

Author

Lien, Fleur, Berthier, Alexandre, Bouchaert, Emmanuel, Gheeraert, Celine, Alexandre, Jeremy, Porez, Geoffrey, Prawitt, Janne, Dehondt, Helene, Ploton, Maheul, Colin, Sophie, Lucas, Anthony, Patrice, Alexandre, Pattou, Francois, Diemer, Helene, Dorsselaer, Alain Van, Rachez, Christophe, Kamilic, Jelena, Groen, Albert K., and Staels, Bart

Subjects
Physiological research, Homeostasis -- Research, Metformin -- Properties, Transcription factors -- Properties, Health care industry
Abstract

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry--based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis., Introduction In addition to their role as lipid emulsifiers, bile acids (BAs) are now also recognized as important regulators of cholesterol, bile acid, and triglyceride and glucose metabolism, as well [...]

Published
2014
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13. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

Author

Dubois, Vanessa, Gheeraert, Celine, Vankrunkelsven, Wouter, Dubois-Chevalier, Julie, Dehondt, Helene, Bobowski-Gerard, Marie, Vinod, Manjula, Zummo, Francesco Paolo, Guiza, Fabian, Ploton, Maheul, Dorchies, Emilie, Pineau, Laurent, Boulinguiez, Alexis, Vallez, Emmanuelle, Woitrain, Eloise, Bauge, Eric, Lalloyer, Fanny, Duhem, Christian, Rabhi, Nabil, van Kesteren, Ronald E, Chiang, Cheng-Ming, Lancel, Steve, Duez, Helene, Annicotte, Jean-Sebastien, Paumelle, Rejane, Vanhorebeek, Ilse, Van den Berghe, Greet, Staels, Bart, Lefebvre, Philippe, Eeckhoute, Jerome, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Intensive care Medicine [Leuven, Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Center for Neurogenomics and Cognitive Research [Amsterdam], Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], University of Texas Southwestern Medical Center [Dallas], European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Derudas, Marie-Hélène, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Molecular and Cellular Neurobiology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Male, Medicine (General), Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chromatin, Epigenetics, Genomics & Functional Genomics, ACTIVATION, sepsis, Mice, ENRICHMENT ANALYSIS, BINDING, Medicine and Health Sciences, Gene Regulatory Networks, Biology (General), Cells, Cultured, GENE-EXPRESSION, Mice, Knockout, Liver Diseases, Nuclear Proteins, super‐enhancer, Articles, CELL IDENTITY, Endoplasmic Reticulum Stress, PAR-bZIP, Up-Regulation, TRANSCRIPTION FACTORS, Basic-Leucine Zipper Transcription Factors, Chromatin Immunoprecipitation Sequencing, Thapsigargin, Chemical and Drug Induced Liver Injury, liver injury, ACETYLATION, QH301-705.5, DATABASE, Down-Regulation, Article, Cell Line, R5-920, SDG 3 - Good Health and Well-being, NFIL3, super-enhancer, Animals, Humans, ELONGATION, Gene Expression Profiling, PAR‐bZIP, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, UNFOLDED PROTEIN, Mice, Inbred C57BL, Gene Expression Regulation, Hepatocytes, Transcriptome, Transcription Factors
Abstract

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver‐identity (LIVER‐ID) transcription factor (TF) network, initiated by rapid LIVER‐ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER‐ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co‐recruitment of LIVER‐ID TFs and decommissioning of BRD4 super‐enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER‐ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients., Functional genomics analyses shows that acute endoplasmic reticulum stress (ERS) in the liver induces a global loss of molecular identity and partial hepatic dedifferentiation, which characterize mouse and human liver upon acute injury.

Published
2020

14. Hepatic molecular signatures highlight the sexual dimorphism of Non-Alcoholic SteatoHepatitis (NASH)

Author

Vandel, Jimmy, Dubois-Chevalier, Julie, Gheeraert, Celine, Derudas, Bruno, Raverdy, Violetta, Thuillier, Dorothée, Van Gaal, Luc, Francque, Sven, Pattou, Francois, Staels, Bart, Eeckhoute, Jérôme, Lefebvre, Philippe, Derudas, Marie-Hélène, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Endocrinology, Diabetology and Metabolism [Antwerp, Belgium], Antwerp University Hospital [Edegem] (UZA), Department of Gastroenterology and Hepatology [Antwerp, Belgium], European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016)

Subjects
Male, Transcriptomic signatures, [SDV]Life Sciences [q-bio], Steatohepatitis and Metabolic Liver Disease, NASH, nutritional and metabolic diseases, Random forest Accepted Article, Original Articles, Middle Aged, digestive system, digestive system diseases, [SDV] Life Sciences [q-bio], Sexual dimorphism, Sex Factors, Liver, Non-alcoholic Fatty Liver Disease, Risk Factors, Humans, Original Article, Female, Obesity, Human medicine, Transcriptome, Random forest
Abstract

Background and Aims Nonalcoholic steatohepatitis (NASH) is considered as a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression, given that it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial, and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex, etc.), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published “omics”‐defined NASH signatures. Approach and Results Here, we have explored transcriptomic profiles of livers starting from a 910‐obese‐patient cohort, which was further stratified based on stringent histological characterization, to define “NoNASH” and “NASH” patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating in distinct biological processes in NASH as a function of sex. RF‐calculated gene signatures identified NASH patients in independent cohorts with high accuracy. Conclusions This large‐scale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.

Published
2020

15. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Author

Mogilenko, Denis A., Haas, Joel T., Lhomme, Laurent, Fleury, Sebastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Helene, Gheeraert, Celine, Melchior, Aurelie, Dewas, Cedric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sebastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria P., Paget, Christophe, Janssens, Sophie, Staumont-Salle, Delphine, Aksoy, Ezra, Staels, Bart, Dombrowicz, David, Mogilenko, Denis A., Haas, Joel T., Lhomme, Laurent, Fleury, Sebastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Helene, Gheeraert, Celine, Melchior, Aurelie, Dewas, Cedric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sebastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria P., Paget, Christophe, Janssens, Sophie, Staumont-Salle, Delphine, Aksoy, Ezra, Staels, Bart, and Dombrowicz, David

Abstract

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondria! reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR., Funding Agencies|ANR; European Union [EGID ANR-10-LABX-46, ANR-17-CE15-0030-02]; National Psoriasis Foundation (USA) Early Career Research Grant; EMBO Long-Term Fellowship; MRC [MR/M023230/1]; CRUK [C29967/A14633, C29967/A26787]; ERC advanced grant (ERC-2016-AdG) [694717]

Published
2019
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16. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Author

Mogilenko, Denis A., primary, Haas, Joel T., additional, L’homme, Laurent, additional, Fleury, Sébastien, additional, Quemener, Sandrine, additional, Levavasseur, Matthieu, additional, Becquart, Coralie, additional, Wartelle, Julien, additional, Bogomolova, Alexandra, additional, Pineau, Laurent, additional, Molendi-Coste, Olivier, additional, Lancel, Steve, additional, Dehondt, Hélène, additional, Gheeraert, Celine, additional, Melchior, Aurelie, additional, Dewas, Cédric, additional, Nikitin, Artemii, additional, Pic, Samuel, additional, Rabhi, Nabil, additional, Annicotte, Jean-Sébastien, additional, Oyadomari, Seiichi, additional, Velasco-Hernandez, Talia, additional, Cammenga, Jörg, additional, Foretz, Marc, additional, Viollet, Benoit, additional, Vukovic, Milica, additional, Villacreces, Arnaud, additional, Kranc, Kamil, additional, Carmeliet, Peter, additional, Marot, Guillemette, additional, Boulter, Alexis, additional, Tavernier, Simon, additional, Berod, Luciana, additional, Longhi, Maria P., additional, Paget, Christophe, additional, Janssens, Sophie, additional, Staumont-Sallé, Delphine, additional, Aksoy, Ezra, additional, Staels, Bart, additional, and Dombrowicz, David, additional

Published
2019
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17. Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR)

Author

Berrabah, Wahiba, Aumercier, Pierrette, Gheeraert, Celine, Dehondt, Helene, Bouchaert, Emmanuel, Alexandre, Jérémy, Ploton, Maheul, Mazuy, Claire, Houde, Sandrine, Muhr Tailleux, Anne, Eeckhoute, Jerome, Lefebvre, Tony, Staels, Bart, Lefebvre, Philippe, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), W.B. was supported by a fellowship from the French Ministry for Education and Research. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, EU grants Hepadip (#018734), A.N.R. (FXRen), European Genomic Institute for Diabetes (E.G.I.D., ANR‐10‐LABX‐46), Région Nord‐Pas de Calais, FEDER and Cost Action BM0602., ANR-11-BSV1-0032,FXRen,Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique(2011), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), and Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Cytoplasmic and Nuclear, Acylation, Hexosamines, Hep G2 Cells, Inbred C57BL, N-Acetylglucosaminyltransferases, Bile Acids and Salts, Pentose Phosphate Pathway, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Mice, Glucose, Gene Expression Regulation, Receptors, Hepatocytes, Humans, Animals, Signal Transduction
Abstract

Bile acid metabolism is intimately linked to the control of energy homeostasis and glucose and lipid metabolism. The nuclear receptor farnesoid X receptor (FXR) plays a major role in the enterohepatic cycling of bile acids, but the impact of nutrients on bile acid homeostasis is poorly characterized. Metabolically active hepatocytes cope with increases in intracellular glucose concentrations by directing glucose into storage (glycogen) or oxidation (glycolysis) pathways, as well as to the pentose phosphate shunt and the hexosamine biosynthetic pathway. Here we studied whether the glucose nonoxidative hexosamine biosynthetic pathway modulates FXR activity. Our results show that FXR interacts with and is O-GlcNAcylated by O-GlcNAc transferase in its N-terminal AF1 domain. Increased FXR O-GlcNAcylation enhances FXR gene expression and protein stability in a cell type-specific manner. High glucose concentrations increased FXR O-GlcNAcylation, hence its protein stability and transcriptional activity by inactivating corepressor complexes, which associate in a ligand-dependent manner with FXR, and increased FXR binding to chromatin. Finally, in vivo fasting-refeeding experiments show that FXR undergoes O-GlcNAcylation in fed conditions associated with increased direct FXR target gene expression and decreased liver bile acid content. CONCLUSION: FXR activity is regulated by glucose fluxes in hepatocytes through a direct posttranslational modification catalyzed by the glucose-sensing hexosamine biosynthetic pathway.

Published
2014

18. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes

Author

Oger, Frederik, Dubois-Chevalier, Julie, Gheeraert, Celine, Avner, Stephane, Durand, Emmanuel, Froguel, Philippe, Salbert, Gilles, Staels, Bart, Lefebvre, Philippe, Eeckhoute, Jerome, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Derudas, Marie-Hélène

Subjects
Epigenomics, MESH: Signal Transduction, MESH: Insulin, chromatin modification, Transcrip tion regulation, MESH: Reverse Transcriptase Polymerase Chain Reaction, DNA methylat ion, MESH: Gene Expression Regulation, Developmental, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Binding, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Somatomedins, MESH: Mice, insulin/insulin-like growth factor signalling, MESH: Adipocytes, MESH: Lipid Metabolism, MESH: Chromatin Immunoprecipitation, Adipogenesis, MESH: Muscle Fibers, Skeletal, MESH: Transcriptome, MESH: 3T3-L1 Cells, MESH: Cell Line, MESH: PPAR gamma, Peroxisome proliferator-activated receptor (PPAR), MESH: Enhancer Elements, Genetic, MESH: Adipogenesis, Transcription enhancers
Abstract

International audience; The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.

Published
2014

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