Author: "Céline Gheeraert" - Searchworks@Jio Institute Digital Library Search Results

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29 results on '"Céline Gheeraert"'

1. O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts

Author: Ninon Very, Clémence Boulet, Céline Gheeraert, Alexandre Berthier, Manuel Johanns, Mohamed Bou Saleh, Loïc Guille, Fabrice Bray, Jean-Marc Strub, Marie Bobowski-Gerard, Francesco P. Zummo, Emmanuelle Vallez, Olivier Molendi-Coste, Eloise Woitrain, Sarah Cianférani, David Montaigne, Line Carolle Ntandja-Wandji, Laurent Dubuquoy, Julie Dubois-Chevalier, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute
Subjects: Cytology, QH573-671
Abstract: Abstract Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.
Published: 2024
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2. Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis

Author: Marie Bobowski-Gerard, Clémence Boulet, Francesco P. Zummo, Julie Dubois-Chevalier, Céline Gheeraert, Mohamed Bou Saleh, Jean-Marc Strub, Amaury Farce, Maheul Ploton, Loïc Guille, Jimmy Vandel, Antonino Bongiovanni, Ninon Very, Eloïse Woitrain, Audrey Deprince, Fanny Lalloyer, Eric Bauge, Lise Ferri, Line-Carolle Ntandja-Wandji, Alexia K. Cotte, Corinne Grangette, Emmanuelle Vallez, Sarah Cianférani, Violeta Raverdy, Robert Caiazzo, Viviane Gnemmi, Emmanuelle Leteurtre, Benoit Pourcet, Réjane Paumelle, Kim Ravnskjaer, Guillaume Lassailly, Joel T. Haas, Philippe Mathurin, François Pattou, Laurent Dubuquoy, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute
Subjects: Science
Abstract: Myofibroblasts contribute to the development of liver fibrosis. Here, the authors report that the transcription factor Basonuclin 2 (BNC2) integrates fibrogenic signals and drives myofibroblastic transcriptional activation in liver fibrosis.
Published: 2022
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3. Pharmacological HDAC inhibition impairs pancreatic β-cell function through an epigenome-wide reprogramming

Author: Frédérik Oger, Maeva Moreno, Mehdi Derhourhi, Bryan Thiroux, Lionel Berberian, Cyril Bourouh, Emmanuelle Durand, Souhila Amanzougarene, Alaa Badreddine, Etienne Blanc, Olivier Molendi-Coste, Laurent Pineau, Gianni Pasquetti, Laure Rolland, Charlène Carney, Florine Bornaque, Emilie Courty, Céline Gheeraert, Jérôme Eeckhoute, David Dombrowicz, Julie Kerr-Conte, François Pattou, Bart Staels, Philippe Froguel, Amélie Bonnefond, and Jean-Sébastien Annicotte
Subjects: Natural sciences, Biological sciences, Molecular biology, Molecular mechanism of gene regulation, Epigenetics, Endocrinology, Science
Abstract: Summary: Histone deacetylases enzymes (HDACs) are chromatin modifiers that regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic β cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic β-cell identity and function using the pan-HDAC inhibitor trichostatin A through chromatin immunoprecipitation assays and RNA sequencing experiments. We observed that TSA alters insulin secretion associated with β-cell specific transcriptome programming in both mouse and human β-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative β-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that HDAC activity could be required to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.
Published: 2023
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4. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

Author: Vanessa Dubois, Céline Gheeraert, Wouter Vankrunkelsven, Julie Dubois‐Chevalier, Hélène Dehondt, Marie Bobowski‐Gerard, Manjula Vinod, Francesco Paolo Zummo, Fabian Güiza, Maheul Ploton, Emilie Dorchies, Laurent Pineau, Alexis Boulinguiez, Emmanuelle Vallez, Eloise Woitrain, Eric Baugé, Fanny Lalloyer, Christian Duhem, Nabil Rabhi, Ronald E van Kesteren, Cheng‐Ming Chiang, Steve Lancel, Hélène Duez, Jean‐Sébastien Annicotte, Réjane Paumelle, Ilse Vanhorebeek, Greet Van den Berghe, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute
Subjects: liver injury, NFIL3, PAR‐bZIP, sepsis, super‐enhancer, Biology (General), QH301-705.5, Medicine (General), R5-920
Abstract: 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.
Published: 2020
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5. Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients

Author: Daniel Margerie, Philippe Lefebvre, Violeta Raverdy, Uwe Schwahn, Hartmut Ruetten, Philip Larsen, Alain Duhamel, Julien Labreuche, Dorothée Thuillier, Bruno Derudas, Céline Gheeraert, Hélène Dehondt, Quentin Dhalluin, Jérémy Alexandre, Robert Caiazzo, Pamela Nesslany, Helene Verkindt, François Pattou, and Bart Staels
Subjects: Statin, Human, Liver, Iatrogenic diabetes, Gene expression, Gene networks, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. Methods An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. Results We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60–4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. Conclusions A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. Trial registration NCT01129297. Registered May 242,010 (retrospectively registered).
Published: 2019
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6. Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis

Author: Fanny Lalloyer, Denis A. Mogilenko, Ann Verrijken, Joel T. Haas, Antonin Lamazière, Mostafa Kouach, Amandine Descat, Sandrine Caron, Emmanuelle Vallez, Bruno Derudas, Céline Gheeraert, Eric Baugé, Gaëtan Despres, Eveline Dirinck, Anne Tailleux, David Dombrowicz, Luc Van Gaal, Jerôme Eeckhoute, Philippe Lefebvre, Jean-François Goossens, Sven Francque, and Bart Staels
Subjects: Hepatology
Published: 2023
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7. A time- and space-resolved nuclear receptor atlas in mouse liver

Author: Francesco Paolo Zummo, Alexandre Berthier, Céline Gheeraert, Manjula Vinod, Marie Bobowski-Gérard, Olivier Molendi-Coste, Laurent Pineau, Matthieu Jung, Loic Guille, Julie Chevalier-Dubois, David Dombrowicz, Bart Staels, Jérôme Eeckhoute, Philippe Lefebvre, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (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), 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), FRM EQU202203014645, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-16-IDEX-0004,ULNE,ULNE(2016), and European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016)
Subjects: Endocrinology, circadian, zonation, [SDV]Life Sciences [q-bio], nuclear receptors liver cell types zonation circadian, nuclear receptors, liver, cell types, Molecular Biology
Abstract: The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics, etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in the liver, we characterized their levels of expression in the whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erba), Nr1d2 (Rev-erbb), Nr1c2 (Pparb/d), and Nr1f3 (Rorg) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxra) and Nr1b1 (Rara) isoforms, was markedly restricted to a few cell types. Leveraging liver single-cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells, and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we provide here an up-to-date compendium of NR expression in mouse liver in space and time.
Published: 2023
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8. The HDAC inhibitor trichostatin A impairs pancreatic β-cell function through an epigenome-wide reprogramming

Author: Frédérik Oger, Maeva Moreno, Mehdi Derhourhi, Bryan Thiroux, Lionel Berberian, Cyril Bourouh, Emmanuelle Durand, Souhila Amanzougarene, Alaa Badreddine, Etienne Blanc, Olivier Molendi-Coste, Laurent Pineau, Gianni Pasquetti, Laure Rolland, Charlène Carney, Florine Bornaque, Emilie Courty, Céline Gheeraert, Jérôme Eeckhoute, David Dombrowicz, Julie Kerr-Conte, François Pattou, Bart Staels, Philippe Froguel, Amélie Bonnefond, and Jean-Sébastien Annicotte
Abstract: ObjectiveThe pancreatic islets of Langerhans contain distinct cell subtypes including insulin-producing β cells. Although their cell-specific gene expression pattern defines their identity, the underlying molecular network driving this transcriptional specificity is not fully understood. Among the numerous transcriptional regulators, histone deacetylases (HDAC) enzymes are potent chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone proteins. The precise molecular mechanisms underlying HDAC effects on cellular plasticity and β-cell identity are currently unknown.MethodsThe pharmacological inhibition of HDAC activity by trichostatin A (TSA) was studied in the mouse Min6 and human EndocBH1 cell lines, as well as primary mouse sorted β cells and human pancreatic islets. The molecular and functional effects of treating these complementary β-cell models with TSA was explored at the epigenomic and transcriptomic level through next-generation sequencing of chromatin immunoprecipitation (ChIP) assays (ChIP-seq) and RNA sequencing (RNA-seq) experiments, respectively.ResultsWe showed that TSA alters insulin secretion associated with β-cell specific transcriptome programming in both mouse and human β-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative β-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers.ConclusionsTaken together, our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.
Published: 2022
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9. Timed use of digoxin prevents heart ischemia-reperfusion injury through a REV-ERBα-UPS signaling pathway

Author: Manjula Vinod, Alexandre Berthier, Xavier Maréchal, Céline Gheeraert, Raphaël Boutry, Stéphane Delhaye, Jean-Sébastien Annicotte, Hélène Duez, Agnès Hovasse, Sarah Cianférani, David Montaigne, Jérôme Eeckhoute, Bart Staels, Philippe Lefebvre, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (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), CHU Lille, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Leducq Foundation LEAN Network 16CVD01, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-46-CE14-0001,VasCal, ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Derudas, Marie-Hélène, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, - - VasCalANR-46-CE14-0001 - INCOMING, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, and 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
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: International audience; Myocardial ischemia–reperfusion injury (MIRI) induces life-threatening damages to the cardiac tissue, and pharmacological means to achieve cardioprotection are sorely needed. MIRI severity varies along the day–night cycle and is molecularly linked to components of the cellular clock, including the nuclear receptor REV-ERBα, a transcriptional repressor. Here we show that digoxin administration in mice is cardioprotective when timed to trigger REV-ERBα protein degradation. In cardiomyocytes, digoxin increases REV-ERBα ubiquitinylation and proteasomal degradation, which depend on REV-ERBα’s ability to bind its natural ligand, heme. Inhibition of the membrane-bound Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation. In untreated cardiomyocytes, REV-ERBα proteolysis is controlled by several E3 ubiquitin ligases and the proteasome subunit PSMB5. Among these, only SIAH2 and PSMB5 contributed to digoxin-induced degradation of REV-ERBα. Thus, controlling REV-ERBα proteostasis through the ubiquitin–proteasome system is an appealing cardioprotective strategy. Our data support the timed use of clinically approved cardiotonic steroids in prophylactic cardioprotection.
Published: 2022
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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: Hélène Duez, Jérôme Eeckhoute, Mohamed Koussa, Catherine Piveteau, Céline Gheeraert, Bart Staels, Claire Seunes, Thomas Modine, Charlotte Potelle, Sandro Ninni, David Montaigne, Cedric Klein, Xavier Marechal, Staniel Ortmans, Alexandre Berthier, Augustin Coisne, Rebecca Deprez, Jean-Louis Edmé, Philippe Lefebvre, Benoit Deprez, Stéphanie Mouton, Dominique Lacroix, Georges Fayad, and Bruno Jegou
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Myocardial Reperfusion Injury, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Aortic valve replacement, medicine, Humans, Myocardial infarction, Propensity Score, Aged, Morning, Aged, 80 and over, Heart Valve Prosthesis Implantation, Ejection fraction, business.industry, Incidence, Aortic Valve Stenosis, General Medicine, Perioperative, Middle Aged, medicine.disease, Circadian Rhythm, Cardiac surgery, Treatment Outcome, 030104 developmental biology, Case-Control Studies, Heart failure, Anesthesia, Nuclear Receptor Subfamily 1, Group D, Member 1, Female, business, Signal Transduction, Cohort study
Abstract: Summary Background On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia–reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. Methods We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia–reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia–reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. Findings In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32–0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68–0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning–afternoon variation in hypoxia–reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia–reoxygenation myocardial injury, Rev-Erb α gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia–reperfusion injury modulator CDKN1a/p21. Interpretation Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. Funding Fondation de France, Federation Francaise de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longevite.
Published: 2018
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11. Transcriptional Network Analysis Implicates Altered Hepatic Immune Function in NASH development and resolution

Author: Audrey Deprince, David Dombrowicz, Artemii Nikitin, Bart Staels, Ann Driessen, Sébastien Fleury, An Verrijken, Denis A. Mogilenko, Hélène Dehondt, Samuel Pic, Luisa Vonghia, Bruno Derudas, Sven Francque, Joel T. Haas, Philippe Lefebvre, Luc Van Gaal, Olivier Molendi-Coste, Céline Gheeraert, Lucie Ducrocq-Geoffroy, Eloise Woitrain, 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 Gastroenterology and Hepatology [Antwerp, Belgium], Antwerp University Hospital [Edegem] (UZA), Department of Endocrinology, Diabetology and Metabolism [Antwerp, Belgium], Department of Pathology [Antwerp, Belgium], ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Derudas, Marie-Hélène, and 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
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Transcription, Genetic, Endocrinology, Diabetes and Metabolism, Antigen presentation, Inflammation, Biology, Diet, High-Fat, digestive system, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Non-alcoholic Fatty Liver Disease, Physiology (medical), Internal Medicine, medicine, Cytotoxic T cell, Animals, Humans, Gene Regulatory Networks, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Microarray analysis techniques, Fatty liver, nutritional and metabolic diseases, Cell Biology, Gene signature, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, digestive system diseases, 3. Good health, Mice, Inbred C57BL, Liver, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030211 gastroenterology & hepatology, Human medicine, Steatohepatitis, medicine.symptom
Abstract: Luisa Vonghia and David Dombrowicz equally contributed to the work.; International audience; Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. The presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of patients with NASH before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed non-alcoholic fatty liver disease (NAFLD) reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity on LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intrahepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.
Published: 2019
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12. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Author: Maria P. Longhi, Jörg Cammenga, Kamil R. Kranc, Samuel Pic, David Dombrowicz, Benoit Viollet, Olivier Molendi-Coste, Arnaud Villacreces, C. Becquart, Alexandra M. Bogomolova, Peter Carmeliet, Steve Lancel, Jean-Sébastien Annicotte, Christophe Paget, Joel T. Haas, Cédric Dewas, Julien Wartelle, Simon Tavernier, Luciana Berod, Nabil Rabhi, Seiichi Oyadomari, Laurent Pineau, Milica Vukovic, Bart Staels, Céline Gheeraert, Guillemette Marot, Laurent L'homme, Ezra Aksoy, Sébastien Fleury, Sandrine Quemener, Sophie Janssens, Matthieu Levavasseur, Alexis C. Boulter, Hélène Dehondt, Marc Foretz, Delphine Staumont-Sallé, Talia Velasco-Hernandez, Artemii Nikitin, Denis A. Mogilenko, Aurelie Melchior, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), 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 - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (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), Tokushima University, Linköping University (LIU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Queen Mary University of London (QMUL), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), MOdel for Data Analysis and Learning (MODAL), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille)-Université de Lille, Sciences et Technologies, The University of Florida College of Medicine, Universiteit Gent = Ghent University [Belgium] (UGENT), Helmholtz Centre for Infection Research (HZI), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche Biomédicale des Armées (IRBA), Departement de Physiologie, Faculté de Médecine, EA4484, IFR 114 IMPRT, Université de Lille, Droit et Santé, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fujii Memorial Institute of Medical Sciences [Tokushima, Japan] (Institute of Advanced Medical Sciences), Department of Hematology [Linköping, Sweden] (Institute for Clinical and Experimental Medicine), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Haemato-Oncology [London, UK] (Barts Cancer Institute), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Santé publique : épidémiologie et qualité des soins-EA 2694 (CERIM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, University of Florida College of Medicine [Gainesville, FL, USA], Hannover Medical School [Hannover] (MHH), The William Harvey Research Institute [London, UK] (NIHR Barts Biomedical Research Centre), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100, Institut National de la Santé et de la Recherche Médicale (INSERM), ER Stress and Inflammation [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], and Centre for Biochemical Pharmacology [London, UK] (William Harvey Research Institute)
Subjects: X-Box Binding Protein 1, XBP1, [SDV]Life Sciences [q-bio], Citric Acid Cycle, Inflammation, UPR, Biology, fatty acids, General Biochemistry, Genetics and Molecular Biology, Mice, chemistry.chemical_compound, 03 medical and health sciences, Immune system, 0302 clinical medicine, IL-23, medicine, Animals, metabolic reprogramming, dendritic cells, innate immunity, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mice, Knockout, Hexokinase, 0303 health sciences, Innate immune system, mtROS, hexokinase, Toll-Like Receptors, Dendritic cell, psoriasis, glycolysis, Acquired immune system, Immunity, Innate, Mitochondria, Cell biology, Cellular Microenvironment, chemistry, 030220 oncology & carcinogenesis, Unfolded Protein Response, Unfolded protein response, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Reactive Oxygen Species, 030217 neurology & neurosurgery
Abstract: International audience; 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 mitochondrial 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.
Published: 2019
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13. Hepatic PPARα is critical in the metabolic adaptation to sepsis

Author: Nathalie Hennuyer, Bruno Derudas, Fanny Lalloyer, Céline Gheeraert, Vanessa Legry, Emmanuelle Vallez, Emmanuel Bouchaert, Hélène Dehondt, Bart Staels, Yann Deleye, Dieter Mesotten, Steve Lancel, Greet Van den Berghe, Céline Cudejko, Hervé Guillou, Réjane Paumelle, Sébastien Fleury, Alexandra Montagner, Kristiaan Wouters, Anne Tailleux, Joel T. Haas, Lies Langouche, Jonathan Vanhoutte, Eric Baugé, Pierre Gourdy, David Dombrowicz, Sarra Smati, Walter Wahli, Arnaud Polizzi, Sarah Anissa Hannou, 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)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Intensive care Medicine, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Maastricht University [Maastricht], Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Nanyang Technological University [Singapour], Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), 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, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Interne Geneeskunde, RS: CARIM - R3 - Vascular biology, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: 0301 basic medicine, BACTERIAL, Peroxisome proliferator-activated receptor, nuclear receptors, PROTECTS, sepsis, Mice, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Nuclear receptors, Ketogenesis, GENE-EXPRESSION, chemistry.chemical_classification, Fatty Acids, INTENSIVE INSULIN THERAPY, Bacterial Infections, Adaptation, Physiological, 3. Good health, Liver, SURVIVAL, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030211 gastroenterology & hepatology, lipids (amino acids, peptides, and proteins), hepatocytes, medicine.symptom, medicine.medical_specialty, FATTY-ACID OXIDATION, Inflammation, Article, Sepsis, 03 medical and health sciences, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Medicine [Science], PPAR alpha, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, TOLERANCE, Hepatology, business.industry, Lipid metabolism, Lipid signaling, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Glucose, Metabolism, chemistry, PROLIFERATOR-ACTIVATED RECEPTORS, inflammation, Metabolic control analysis, Hepatocytes, Steatosis, business, metabolism
Abstract: Background & Aims: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)alpha, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPAR alpha in the response to sepsis.Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific PPAR alpha-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPAR alpha expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters.Results: Both whole body and non-hematopoietic PPAR alpha-deficiency in mice decreased survival upon bacterial infection. Livers of septic PPAR alpha-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPAR alpha impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPAR alpha expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.Conclusion: During sepsis, PPAR alpha-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPAR alpha in hepatocytes plays a key role in the host defense against infection.Lay summary: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPAR alpha in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Published: 2019
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14. Nucleotide-binding oligomerization domain 1 (NOD1) modulates liver ischemia reperfusion through the expression adhesion molecules

Author: Sébastien Dharancy, Benjamin Bertin, François Maggiotto, Patrice Maboudou, Florent Artru, Mohamed Bou Saleh, Guillaume Lassailly, Céline Gheeraert, Philippe Mathurin, Rodolphe Carpentier, Didier Betbeder, Emilie Gantier, Laurent Dubuquoy, Natascha Leleu-Chavain, Viviane Gnemmi, Massih Ningarhari, Alexandre Louvet, Lille Inflammation Research International Center - U 995 (LIRIC), 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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, CHU Lille, Inserm, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Lille Inflammation Research International Center - U 995 [LIRIC], and Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Subjects: 0301 basic medicine, Agonist, Necrosis, medicine.drug_class, Neutrophils, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Vascular Cell Adhesion Molecule-1, Liver transplantation, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Lactate dehydrogenase, Nod1 Signaling Adaptor Protein, NOD1, medicine, Animals, Humans, Liver injury, Hepatology, Cell adhesion molecule, medicine.disease, Intercellular Adhesion Molecule-1, Molecular biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, body regions, 030104 developmental biology, medicine.anatomical_structure, chemistry, Liver, Hepatocyte, Reperfusion Injury, 030211 gastroenterology & hepatology, medicine.symptom, Signal Transduction
Abstract: Background & Aims In liver transplantation, organ shortage leads to the use of marginal grafts that are more susceptible to ischemia–reperfusion (IR) injury. We identified nucleotide-binding oligomerization domain 1 (NOD1) as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in IR. Herein, we aimed to elucidate the role of NOD1 in IR injury, particularly focusing on its effects on the endothelium and hepatocytes. Method Nod1 WT and KO mice were treated with NOD1 agonists and subjected to liver IR. Expression of adhesion molecules was analyzed in total liver, isolated hepatocytes and endothelial cells. Interactions between PMNs and hepatocytes were studied in an ex vivo co-culture model using electron microscopy and lactate dehydrogenase levels. We generated NOD1 antagonist-loaded nanoparticles (np ALINO). Results NOD1 agonist treatment increased liver injury, PMN tissue infiltration and upregulated ICAM-1 and VCAM-1 expression 20 hours after reperfusion. NOD1 agonist treatment without IR increased expression of adhesion molecules (ICAM-1, VCAM-1) in total liver and more particularly in WT hepatocytes, but not in Nod1 KO hepatocytes. This induction is dependent of p38 and ERK signaling pathways. Compared to untreated hepatocytes, a NOD1 agonist markedly increased hepatocyte lysis in co-culture with PMNs as shown by the increase of lactate dehydrogenase in supernatants. Interaction between hepatocytes and PMNs was confirmed by electron microscopy. In a mouse model of liver IR, treatment with np ALINO significantly reduced the area of necrosis, aminotransferase levels and ICAM-1 expression. Conclusion NOD1 regulates liver IR injury through induction of adhesion molecules and modulation of hepatocyte-PMN interactions. NOD1 antagonist-loaded nanoparticles reduced liver IR injury and provide a potential approach to prevent IR, especially in the context of liver transplantation. Lay summary Nucleotide-binding oligomerization domain 1 (NOD1) is as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in ischemia-reperfusion. Here, we show that the NOD1 pathway targets liver adhesion molecule expression on the endothelium and on hepatocytes through p38 and ERK signaling pathways. The early increase of adhesion molecule expression after reperfusion emphasizes the importance of adhesion molecules in liver injury. In this study we generated nanoparticles loaded with NOD1 antagonist. These nanoparticles reduced liver necrosis by reducing PMN liver infiltration and adhesion molecule expression.
Published: 2019
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15. Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex

Author: Agnès Hovasse, Manjula Vinod, Jérôme Eeckhoute, Jeremy Alexandre, Alexandre Berthier, Julie Dubois-Chevalier, Fabrice Bray, Maheul Ploton, Xavier Marechal, Bart Staels, Christine Schaeffer-Reiss, Agata Steenackers, Hélène Duez, Philippe Lefebvre, Geoffrey Porez, Sarah Cianférani, Christian Rolando, Nao Yamakawa, Céline Gheeraert, Tony Lefebvre, 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), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrgan [Université de Strasbourg], Université de Strasbourg (UNISTRA), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires - CNRS FR3688 (FRABio), Institut Michel Eugène Chevreul - FR 2638 (IMEC), Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by Agence Nationale de la Recherche Grants OGlcRev and ANR-10-LABX-46, Fondation pour la Recherche Médicale Grant Equipe labellisée FRM 2015 DEQ20150331724, European Foundation for the Study of Diabetes/Lilly European Diabetes Research Program, European Commission EuRhythDia FP7-health Grant 278397, and French Proteomic Infrastructure Grant ANR-10-INBS-08–03. B.S. is a recipient of Advanced European Council Grant 694717. OGlcNAcylated protein identification was done at 'Plateforme Analyses Glycoconjugués' (FR3688 FRABio, CNRS, Université de Lille)., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), European Project: 278397,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,EURHYTHDIA(2011), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Inserm, Université de Lille, CHU Lille, CNRS, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Institut Pluridisciplinaire Hubert Curien [IPHC], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] [LSMBO], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour l'Analyse, la Synthèse & la Protéomique (USR CNRS 3290), Centre National de la Recherche Scientifique (CNRS), Fédération de Recherche Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires (FRABio - CNRS FR3688), Institut Michel Eugène Chevreul [Villeneuve d’Ascq] (CNRS FR 2638), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, ANR-10-LABX-0046/10-LABX-0046,EGID,EGID Diabetes Pole(2010), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - USR 3290 (MSAP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Institut de Chimie du CNRS (INC), Université d'Artois (UA)-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centrale Lille Institut (CLIL), Derudas, Marie-Hélène, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Chronotherapeutic lifestyle intervention for diabetes and obesity to reset the circadian rhythm and improve cardiometabolic risk in the European working population - EURHYTHDIA - - EC:FP7:HEALTH2011-10-01 - 2017-06-30 - 278397 - VALID, 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, and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, viruses, Circadian clock, N-Acetylglucosaminyltransferases, Biochemistry, Mice, 03 medical and health sciences, O-GlcNAcylation, REV-ERBα, Cell Line, Tumor, Circadian Clocks, Gene expression, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Insulin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, Nuclear protein, Protein kinase B, Mice, Knockout, Multidisciplinary, biology, Kinase, Chemistry, Hep G2 Cells, Biological Sciences, Lipid Metabolism, Cell biology, Mice, Inbred C57BL, Insulin receptor, Glucose, HEK293 Cells, 030104 developmental biology, PNAS Plus, Gene Expression Regulation, Liver, Nuclear receptor, Regulatory sequence, epigenomics, metabolism, Signal Transduction, Nuclear Receptor Subfamily 1, Group D, Member 1, biology.protein, Sterol Regulatory Element Binding Protein 1, Proto-Oncogene Proteins c-akt, signal transduction
Abstract: Significance Using an interactomic approach, we have identified the nuclear receptor REV-ERBα as a O-GlcNAc transferase (OGT) protein partner. REV-ERBα protects cytoplasmic OGT from proteasomal degradation and facilitates cytosolic and nuclear protein O-GlcNAcylation while REV-ERα ligands decreased cytoplasmic OGT activity. REV-ERBα thus exerts pleiotropic activities through OGT, coordinating signal transduction, epigenomic programming, and transcriptional response in the liver., The nuclear receptor REV-ERBα integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBα−interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBα cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBα ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBα controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBα expression. REV-ERBα enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites. As an example, we show that the REV-ERBα/OGT complex modulates SREBP-1c gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the Srebf1 promoter for a further rapid response to insulin. Conclusion: REV-ERBα regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic SREBF1 locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic SREBP-1c transcript.
Published: 2018
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16. The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis

Author: Maheul Ploton, Claire Mazuy, Céline Gheeraert, Vanessa Dubois, Alexandre Berthier, Julie Dubois-Chevalier, Xavier Maréchal, Kadiombo Bantubungi, Hélène Diemer, Sarah Cianférani, Jean-Marc Strub, Audrey Helleboid-Chapman, Jérôme Eeckhoute, Bart Staels, Philippe Lefebvre
Published: 2018
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17. The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPARγ

Author: François F, Firmin, Frederik, Oger, Céline, Gheeraert, Julie, Dubois-Chevalier, Anne-Sophie, Vercoutter-Edouart, Fawaz, Alzaid, Claire, Mazuy, Hélène, Dehondt, Jeremy, Alexandre, Bruno, Derudas, Quentin, Dhalluin, Maheul, Ploton, Alexandre, Berthier, Eloise, Woitrain, Tony, Lefebvre, Nicolas, Venteclef, François, Pattou, Bart, Staels, Jérôme, Eeckhoute, Philippe, Lefebvre, Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Fédération de Recherche Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires (FRABio - CNRS FR3688), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche translationelle sur le diabète (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut Européen de Génomique du Diabète - EGID, 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)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires - CNRS FR3688 (FRABio), Université de Lille-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche translationnelle sur le diabète - U 1190 (RTD), 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), Derudas, Marie-Hélène, and École Pratique des Hautes Études (EPHE)
Subjects: Adult, Transcription, Genetic, [SDV]Life Sciences [q-bio], lcsh:Medicine, Article, Body Mass Index, Mice, Adipocytes, Animals, Humans, Obesity, lcsh:Science, Cell Nucleus, Inflammation, Adipogenesis, lcsh:R, Intracellular Signaling Peptides and Proteins, Mesenchymal Stem Cells, 3T3 Cells, Middle Aged, PPAR gamma, [SDV] Life Sciences [q-bio], Disease Models, Animal, Female, RNA, Long Noncoding, lcsh:Q, Transcription Factors
Abstract: International audience; Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.
Published: 2017
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18. The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions

Author: Jason S. Carroll, Nathalie Hennuyer, Bruno Derudas, Eric Baugé, Parisa Mazrooei, Aurélien A. Sérandour, Julie Dubois-Chevalier, Jérôme Eeckhoute, Bart Staels, Guillemette Marot, Philippe Lefebvre, Mathieu Lupien, Céline Gheeraert, Vanessa Dubois, Penderia Guillaume, Hélène Dehondt, Réjane Paumelle, Claire Mazuy, Université de Lille, Droit et Santé, 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 Medical Biophysics (MBP), University of Toronto, University of Cambridge [UK] (CAM), MOdel for Data Analysis and Learning (MODAL), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Carroll, Jason [0000-0003-3643-0080], Apollo - University of Cambridge Repository, Marot, Guillemette, 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, CHU Lille, INSERM, Inserm, Université de Lille, Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Department of Medical Biophysics [MBP], University of Cambridge [UK] [CAM], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Paul Painlevé - UMR 8524 (LPP), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille)
Subjects: 0301 basic medicine, Transcription, Genetic, Cytoplasmic and Nuclear/deficiency, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Mice, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Receptors, Transcriptional regulation, Regulatory Elements, Transcriptional, Genetics (clinical), Epigenomics, Cis-regulatory module, Regulation of gene expression, Mice, Knockout, PPAR alpha/deficiency, [STAT.ME] Statistics [stat]/Methodology [stat.ME], [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genome, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], Liver, Transcriptional, Transcription, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Algorithms, Liver/metabolism, Knockout, Computational biology, PPAR alpha/genetics, Biology, 03 medical and health sciences, Genetic, Genetics, Animals, PPAR alpha, Enhancer, Gene, Gene Expression Profiling, fungi, Regulatory Elements, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Genomics/methods, Gene expression profiling, 030104 developmental biology, Gene Expression Regulation, Cytoplasmic and Nuclear/genetics, 030217 neurology & neurosurgery
Abstract: Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.
Published: 2017
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19. Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR)

Author: Claire Mazuy, Tony Lefebvre, Wahiba Berrabah, Anne Tailleux, Maheul Ploton, Philippe Lefebvre, Jérôme Eeckhoute, Jeremy Alexandre, Emmanuel Bouchaert, Hélène Dehondt, Bart Staels, Pierrette Aumercier, Céline Gheeraert, and Sandrine Caron
Subjects: 0303 health sciences, Hepatology, Bile acid, Glycogen, medicine.drug_class, Pentose phosphate pathway, Biology, G protein-coupled bile acid receptor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Nuclear receptor, Biochemistry, chemistry, 030220 oncology & carcinogenesis, medicine, Glycolysis, Farnesoid X receptor, Signal transduction, 030304 developmental biology
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. (Hepatology 2014;59:2022–2033)
Published: 2014
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20. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

Author: Geoffrey Porez, Fleur Lien, Hélène Dehondt, Alain Van Dorsselaer, Hélène Diemer, Emmanuel Bouchaert, Alexandre Berthier, Alexandre Patrice, Bart Staels, Jelena Kamilic, Céline Gheeraert, Albert K. Groen, Jeremy Alexandre, Anthony Lucas, François Pattou, Maheul Ploton, Janne Prawitt, Philippe Lefebvre, Sophie Colin, Christophe Rachez, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)
Subjects: Male, Transcription, Genetic, Receptors, Cytoplasmic and Nuclear, TRANSCRIPTIONAL ACTIVITY, Homeostasis, Glucose homeostasis, Intestinal Mucosa, Phosphorylation, Promoter Regions, Genetic, Enterohepatic circulation, POSTTRANSLATIONAL MODIFICATIONS, Bile acid, ACTIVATED PROTEIN-KINASE, Hep G2 Cells, General Medicine, G protein-coupled bile acid receptor, Metformin, Intestines, Liver, LIVER-INJURY, Signal transduction, FARNESOID-X-RECEPTOR, Protein Binding, Signal Transduction, Research Article, Transcriptional Activation, ORPHAN NUCLEAR RECEPTOR, medicine.medical_specialty, medicine.drug_class, CELLULAR-ENERGY, Molecular Sequence Data, Cholestasis, Intrahepatic, Biology, Bile Acids and Salts, Cholestasis, Internal medicine, medicine, Animals, Humans, Hypoglycemic Agents, Amino Acid Sequence, Adenylate Kinase, AMPK, Biological Transport, Ribonucleotides, Aminoimidazole Carboxamide, medicine.disease, Mice, Inbred C57BL, OBSTRUCTIVE CHOLESTASIS, MICE, Endocrinology, Trans-Activators, Farnesoid X receptor, GLUCOSE-HOMEOSTASIS, Caco-2 Cells, Protein Processing, Post-Translational
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 e 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.
Published: 2014

21. Author Correction: Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution

Author: Luisa Vonghia, Eloise Woitrain, Olivier Molendi-Coste, Hélène Dehondt, Philippe Lefebvre, Denis A. Mogilenko, Ann Driessen, Samuel Pic, Sébastien Fleury, Bruno Derudas, Luc Van Gaal, David Dombrowicz, Bart Staels, Sven Francque, Céline Gheeraert, Lucie Ducrocq-Geoffroy, Artemii Nikitin, An Verrijken, Audrey Deprince, and Joel T. Haas
Subjects: Computer science, Physiology (medical), Endocrinology, Diabetes and Metabolism, Resolution (electron density), Internal Medicine, Cell Biology, Computational biology, Network analysis
Abstract: In the version of this article initially published, ANR grant ANR-16-RHUS-0006 to author Joel T. Haas was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.
Published: 2019
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22. 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: Stéphane Avner, Philippe Froguel, Bart Staels, Gilles Salbert, Philippe Lefebvre, Frédérik Oger, Jérôme Eeckhoute, Julie Dubois-Chevalier, Emmanuelle Durand, Céline Gheeraert, 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), 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), 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)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: Epigenomics, MESH: Signal Transduction, Muscle Fibers, Skeletal, Peroxisome proliferator-activated receptor, Enhancer RNAs, Biochemistry, Mice, chromatin modification, Transcrip tion regulation, MESH: Reverse Transcriptase Polymerase Chain Reaction, DNA methylat ion, MESH: Gene Expression Regulation, Developmental, Adipocytes, Insulin, MESH: Animals, insulin/insulin-like growth factor signalling, MESH: Lipid Metabolism, MESH: Chromatin Immunoprecipitation, chemistry.chemical_classification, Adipogenesis, MESH: Muscle Fibers, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Developmental, Enhancer Elements, Genetic, Signal transduction, Transcription enhancers, Protein Binding, Signal Transduction, Chromatin Immunoprecipitation, MESH: Insulin, Biology, Cell Line, Somatomedins, 3T3-L1 Cells, Animals, MESH: Protein Binding, Gene Regulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Somatomedins, Enhancer, MESH: Mice, Molecular Biology, Transcription factor, MESH: Adipocytes, MESH: Transcriptome, Lipid metabolism, Cell Biology, Lipid Metabolism, MESH: 3T3-L1 Cells, MESH: Cell Line, PPAR gamma, MESH: PPAR gamma, Nuclear receptor, chemistry, Peroxisome proliferator-activated receptor (PPAR), MESH: Enhancer Elements, Genetic, Transcriptome, MESH: Adipogenesis
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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23. Inactivation of the Nuclear Orphan Receptor COUP-TFII by Small Chemicals

Author: Gilles Salbert, François F. Firmin, Bart Staels, Iannis Talianidis, Philippe Lefebvre, Frédérik Oger, Miroslava Kretova, Maheul Ploton, Jérôme Eeckhoute, Celia P. Martinez-Jimenez, Gaëlle Palierne, Maud Bizot, Rémy Le Guével, Céline Gheeraert, Peter Barath, Jonchère, Laurent, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, 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 ), 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, Institute of Immunology, Biomedical Sciences Research Center Al. Fleming, Slovak Academy of Science [Bratislava] (SAS), This work was funded by the European Community (QLG1-CT-2001-01513), the Centre National pour la Recherche Scientifique and the Ministère de l’Enseignement Supérieur et de la Recherche. This work was also supported by grants from 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46). F.O. and C.G. were supported by OSEO-ANVAR (IT-DIAB). B.S. is a member of the Institut Universitaire de France., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [SDV.GEN] Life Sciences [q-bio]/Genetics, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, COUP Transcription Factor II, Small Molecule Libraries, Mice, 03 medical and health sciences, 0302 clinical medicine, 3T3-L1 Cells, Adipocytes, Animals, Humans, Binding site, Transcription factor, COUP-TFII, Orphan receptor, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, biology, Cell Differentiation, Hep G2 Cells, General Medicine, Small molecule, 3. Good health, Neuron-derived orphan receptor 1, Ovalbumin, 030104 developmental biology, Nuclear receptor, biology.protein, Molecular Medicine, 030217 neurology & neurosurgery
Abstract: International audience; Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan member of the nuclear receptor family of transcription factors whose activities are modulated upon binding of small molecules into an hydrophobic ligand-binding pocket (LBP). Although the LBP of COUP-TFII is filled with aromatic amino-acid side chains, alternative modes of ligand binding could potentially lead to regulation of the orphan receptor. Here, we screened a synthetic and natural compound library in a yeast one-hybrid assay and identified 4-methoxynaphthol as an inhibitor of COUP-TFII. This synthetic inhibitor was able to counteract processes either positively or negatively regulated by COUP-TFII in different mammalian cell systems. Hence, we demonstrate that the true orphan receptor COUP-TFII can be targeted by small chemicals which could be used to study the physiological functions of COUP-TFII or to counteract detrimental COUP-TFII activities in various pathological conditions.
Published: 2017
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24. The logic of transcriptional regulator recruitment architecture at

Author: Julie, Dubois-Chevalier, Vanessa, Dubois, Hélène, Dehondt, Parisa, Mazrooei, Claire, Mazuy, Aurélien A, Sérandour, Céline, Gheeraert, Penderia, Guillaume, Eric, Baugé, Bruno, Derudas, Nathalie, Hennuyer, Réjane, Paumelle, Guillemette, Marot, Jason S, Carroll, Mathieu, Lupien, Bart, Staels, Philippe, Lefebvre, and Jérôme, Eeckhoute
Subjects: Mice, Knockout, Genome, Transcription, Genetic, Gene Expression Profiling, Research, fungi, Receptors, Cytoplasmic and Nuclear, Genomics, Mice, Gene Expression Regulation, Liver, Animals, PPAR alpha, Regulatory Elements, Transcriptional, Algorithms
Abstract: Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.
Published: 2016

25. The Novel Antibacterial Compound Walrycin A Induces Human PXR Transcriptional Activity

Author: Céline Gheeraert, Alexandre Berthier, Rémy Le Guével, Gilles Salbert, Patrick Balaguer, Philippe Lefebvre, Bart Staels, Abdel Boulahtouf, Frédérik Oger, 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), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique fonctionnelle, agronomie et santé (GFAS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), and Derudas, Marie-Hélène
Subjects: Receptors, Steroid, CYP3A4, Gene Expression, Quantitative Structure-Activity Relationship, Naphthols, Walrycin A, Toxicology, MESH: Hepatocytes, Transactivation, 0302 clinical medicine, MESH: RNA, Small Interfering, Gene expression, Cytochrome P-450 CYP3A, Xenobiotic, RNA, Small Interfering, Cell Line, Transformed, Oligonucleotide Array Sequence Analysis, MESH: Cytochrome P-450 CYP3A, MESH: Quantitative Structure-Activity Relationship, 0303 health sciences, Pregnane X receptor, MESH: Real-Time Polymerase Chain Reaction, Pregnane X Receptor, Transfection, Anti-Bacterial Agents, 3. Good health, MESH: Cell Survival, Biochemistry, 030220 oncology & carcinogenesis, Rifampin, Signal transduction, Protein Binding, MESH: Computational Biology, MESH: Gene Expression, Cell Survival, Biology, Real-Time Polymerase Chain Reaction, digestive system, Article, 03 medical and health sciences, MESH: Computer Simulation, MESH: Anti-Bacterial Agents, Ligand Binding Domain, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: Protein Binding, Computer Simulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Cell Line, Transformed, Transcription factor, 030304 developmental biology, MESH: Humans, MESH: Naphthols, Activator (genetics), MESH: Transfection, Computational Biology, MESH: Rifampin, digestive system diseases, Nuclear receptor, MESH: Oligonucleotide Array Sequence Analysis, Hepatocytes, Nuclear Receptor, MESH: Receptors, Steroid
Abstract: International audience; The human pregnane X receptor (PXR) is a ligand-regulated transcription factor belonging to the nuclear receptor superfamily. PXR is activated by a large, structurally diverse, set of endogenous and xenobiotic compounds and coordinates the expression of genes central to metabolism and excretion of potentially harmful chemicals and therapeutic drugs in humans. Walrycin A is a novel antibacterial compound targeting the WalK/WalR two-component signal transduction system of Gram (+) bacteria. Here, we report that, in hepatoma cells, walrycin A potently activates a gene set known to be regulated by the xenobiotic sensor PXR. Walrycin A was as efficient as the reference PXR agonist rifampicin to activate PXR in a transactivation assay at noncytotoxic concentrations. Using a limited proteolysis assay, we show that walrycin A induces conformational changes at a concentration which correlates with walrycin A ability to enhance the expression of prototypic target genes, suggesting that walrycin A interacts with PXR. The activation of the canonical human PXR target gene CYP3A4 by walrycin A is dose and PXR dependent. Finally, in silico docking experiments suggest that the walrycin A oxidation product Russig's blue is the actual ligand for PXR. Taken together, these results identify walrycin A as a novel human PXR activator.
Published: 2012
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26. Surexpression kératinocytaire de PPARß/δ chez la souris : un modèle de psoriasis ?

Author: Céline Gheeraert, Quentin Dhalluin, Philippe Lefebvre, Olivier Molendi-Coste, Denis A. Mogilenko, David Dombrowicz, Laurent Pineau, Sébastien Fleury, Bart Staels, Barbara Gross, F. Dezoteux, Sandrine Quemener, and Delphine Staumont-Sallé
Subjects: Chemistry, Dermatology, Molecular biology
Abstract: Introduction Le psoriasis est une maladie inflammatoire chronique de la peau frequemment associee a des comorbidites metaboliques. Le recepteur nucleaire peroxisome proliferator activator receptor (PPARβ/δ) est un regulateur de l’homeostasie metabolique. De plus, sa surexpression dans les keratinocytes est associee au psoriasis. Ainsi, il represente un candidat potentiel expliquant le lien entre psoriasis et metabolisme. Materiel et methodes Un nouveau modele murin surexprimant PPARβ/δ specifiquement dans les keratinocytes, (souris K14PPARβ/δ Tg), a ete developpe au sein de notre unite afin d’etudier cette association. Le phenotype cutane des souris K14PPARβ/δ Tg a ete caracterise en etudiant la permeabilite de la barriere cutanee par des techniques colorimetriques et immunohistochimiques (filaggrine), l’inflammation cutanee (analyse des populations cellulaires par cytometrie de flux et de l’expression de cytokines dans la peau) et les mecanismes moleculaires de l’inflammation notamment par biopuce pangenomique. Resultats Les souris K14PPARβ/δ Tg developpent une reaction inflammatoire cutanee des 5 jours de vie. L’evolution est marquee par l’aggravation des lesions et une letalite precoce a l’âge d’une semaine sans pouvoir incriminer un probleme de prise alimentaire, ni une alteration de la barriere cutanee. Les lesions cutanees des souris sont similaires au psoriasis chez l’homme, tant sur le plan macroscopique qu’histologique. Il existe, cependant, des differences concernant le profil cytokinique avec notamment une expression accrue d’interleukine 4 et 33. Les lesions cutanees sont de nature inflammatoire avec un infiltrat de cellules de l’immunite innee marque par une predominance de mastocytes, de polynucleaires neutrophiles et de cellules dendritiques. Etonnamment, les cellules lymphocytaires T classiquement impliquees dans le developpement du psoriasis ne sont pas presentes dans la peau des souris K14PPARβ/δ Tg, ce qui peut etre explique par l’immaturite du systeme immunitaire chez la souris âgee de 5 jours. L’analyse transcriptomique par biopuce a mis en evidence dans la peau des souris K14PPARβ/δ Tg un profil d’expression genique proche de celui des lesions de psoriasis avec une surexpression de genes intervenant dans la proliferation et la differenciation keratinocytaire mais egalement aussi des genes de l’inflammation. Discussion Ce travail a permis de montrer que les souris K14PPARβ/δ Tg a l’âge de 5 jours presentent des lesions inflammatoires cutanees qui pourraient s’apparenter a du psoriasis a un stade precoce de la reponse inflammatoire du fait de l’absence de cellules lymphocytaires classiques. Conclusion Au total, notre modele presente des caracteristiques se rapprochant du psoriasis. Cependant, la survenue de la letalite precoce des souris K14PPARβ/δ Tg, dont l’origine reste inconnue, rend impossible l’etude des parametres metaboliques chez ces animaux.
Published: 2016
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27. The hepatic orosomucoid/α1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR

Author: Geoffrey Porez, Janne Prawitt, Jeremy Alexandre, Céline Gheeraert, Bart Staels, Barbara Gross, Wahiba Berrabah, and Philippe Lefebvre
Subjects: Male, medicine.medical_specialty, medicine.drug_class, Adipose Tissue, White, Response element, Receptors, Cytoplasmic and Nuclear, Mice, Transgenic, Biology, Response Elements, Cell Line, Mice, Endocrinology, Species Specificity, Internal medicine, Gene cluster, medicine, Animals, Humans, Protein Isoforms, Receptor, Regulation of gene expression, Mice, Knockout, Bile acid, Orosomucoid, G protein-coupled bile acid receptor, Recombinant Proteins, Rats, Mice, Inbred C57BL, Nuclear receptor, Gene Expression Regulation, Organ Specificity, Multigene Family, Hepatocytes, Farnesoid X receptor
Abstract: The α-1-acid glycoprotein/orosomucoids (ORMs) are members of the lipocalin protein family. Encoded by 3 polymorphic genes in mouse (2 in man, 1 in rat), ORMs are expressed in hepatocytes and function as acute-phase proteins secreted in plasma under stressful conditions. In addition to their role of nanocarrier, ORMs are involved in several pathophysiological processes such as immunosuppression, cardioprotection, and inflammatory bowel disease. The nuclear bile acid receptor farnesoid X receptor (FXR) regulates bile acid homeostasis and lipid and glucose metabolism and is an important modulator of enterohepatic functions. Here we report that hepatic FXR deletion in mice affects the expression of several members of the lipocalin family, among which ORMs are identified as direct FXR target genes. Indeed, a FXR response element upstream of the mouse Orm1 promoter was identified to which hepatic, but not ileal, FXR can bind and activate ORM expression in vitro and in vivo. However, ORMs are regulated in a species-specific manner because the ORM cluster is regulated by FXR neither in human nor rat cell lines. Consistent with these data, chromatin immunoprecipitation sequencing analysis of the FXR genomic binding sites did not detect any FXR response element in the vicinity of the human or rat ORM gene cluster. Thus, bile acids and their cognate nuclear receptor, FXR, are regulators of ORM expression, with potential implications for the species-specific metabolic and inflammation control by FXR because the expression of the proinflammatory genes in epididymal white adipose tissue was dependent on liver FXR activation.
Published: 2013

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

Author: Wahiba, Berrabah, Pierrette, Aumercier, Céline, Gheeraert, Hélène, Dehondt, Emmanuel, Bouchaert, Jérémy, Alexandre, Maheul, Ploton, Claire, Mazuy, Sandrine, Caron, Anne, Tailleux, Jérôme, Eeckhoute, Tony, Lefebvre, Bart, Staels, and Philippe, Lefebvre
Subjects: Male, Acylation, Receptors, Cytoplasmic and Nuclear, Hexosamines, Hep G2 Cells, N-Acetylglucosaminyltransferases, Bile Acids and Salts, Mice, Inbred C57BL, Pentose Phosphate Pathway, Mice, Glucose, Gene Expression Regulation, Hepatocytes, Animals, Humans, 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.FXR activity is regulated by glucose fluxes in hepatocytes through a direct posttranslational modification catalyzed by the glucose-sensing hexosamine biosynthetic pathway.
Published: 2013

29. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers

Author: Raphaël Métivier, Philippe Froguel, Gaëlle Palierne, Jérôme Eeckhoute, Frédérik Oger, Céline Lucchetti-Miganeh, Bart Staels, Emmanuelle Durand, Frédérique Barloy-Hubler, Aurélien A. Sérandour, Stéphane Avner, Frédéric Percevault, Maud Bizot, Thierry Madigou, Gilles Salbert, Philippe Lefebvre, Céline Gheeraert, Christine Le Péron, De Villemeur, Hervé, 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 ), 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), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), The Ligue National Contre le Cancer [Equipe Labellisée Ligue 2009 to G.S.], the Agence Nationale pour la Recherche [ANR-09-BLAN-0268-01 to G.S.], the Région Bretagne [CREATE-DYNAMED-4793 to R.M. and SAD 08HC-315-02 to J.E.], F.O. and C.G. were supported by OSEO-ANVAR [IT-DIAB], A.A.S. was a recipient of a PhD fellowship from the Ministère de la Recherche. Funding for open access charge: CNRS., Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: MESH: Neoplasm Proteins, MESH: Cytosine, Cellular differentiation, Enhancer RNAs, Mice, 0302 clinical medicine, MESH: DNA Methylation, MESH: Animals, Myeloid Ecotropic Viral Integration Site 1 Protein, 0303 health sciences, Cell Differentiation, MESH: Transcription Factors, Chromatin, Cell biology, Neoplasm Proteins, DNA-Binding Proteins, P19 cell, Enhancer Elements, Genetic, DNA methylation, 5-Methylcytosine, DNA Hydroxymethylation, MESH: Cell Differentiation, MESH: Cell Line, Tumor, Neurogenesis, Biology, Gene Regulation, Chromatin and Epigenetics, MESH: Chromatin, 03 medical and health sciences, Cytosine, 3T3-L1 Cells, Cell Line, Tumor, Proto-Oncogene Proteins, MESH: Homeodomain Proteins, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enhancer, Transcription factor, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, Binding Sites, DNA Methylation, Molecular biology, MESH: 3T3-L1 Cells, MESH: Neurogenesis, MESH: Proto-Oncogene Proteins, MESH: Binding Sites, MESH: Enhancer Elements, Genetic, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Enhancers are developmentally controlled transcriptional regulatory regions whose activities are modulated through histone modifications or histone variant deposition. In this study, we show by genome-wide mapping that the newly discovered deoxyribonucleic acid (DNA) modification 5-hydroxymethylcytosine (5hmC) is dynamically associated with transcription factor binding to distal regulatory sites during neural differentiation of mouse P19 cells and during adipocyte differentiation of mouse 3T3-L1 cells. Functional annotation reveals that regions gaining 5hmC are associated with genes expressed either in neural tissues when P19 cells undergo neural differentiation or in adipose tissue when 3T3-L1 cells undergo adipocyte differentiation. Furthermore, distal regions gaining 5hmC together with H3K4me2 and H3K27ac in P19 cells behave as differentiation-dependent transcriptional enhancers. Identified regions are enriched in motifs for transcription factors regulating specific cell fates such as Meis1 in P19 cells and PPARγ in 3T3-L1 cells. Accordingly, a fraction of hydroxymethylated Meis1 sites were associated with a dynamic engagement of the 5-methylcytosine hydroxylase Tet1. In addition, kinetic studies of cytosine hydroxymethylation of selected enhancers indicated that DNA hydroxymethylation is an early event of enhancer activation. Hence, acquisition of 5hmC in cell-specific distal regulatory regions may represent a major event of enhancer progression toward an active state and participate in selective activation of tissue-specific genes.
Published: 2012
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29 results on '"Céline Gheeraert"'

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21. Author Correction: Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution

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

29. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers

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29 results on '"Céline Gheeraert"'

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