Inter-organ cross-talk in cardiometabolic diseases

Team 1 – INSERM U1011 – Lille University – CHU Lille – Institut Pasteur de Lille

équipe recherche u1011 bart staels

Presentation

The organism senses its energy status through a close organ communication (liver, adipose tissue, intestine, pancreas), which integrate multiple endocrine (hormones, inflammatory cytokines) and metabolic (glucose, free fatty acids and intermediary metabolites) signals. Dysregulation of the tight control of metabolism leads to dyslipidemia, diabetes, obesity and non-alcoholic fatty liver disease, which predispose to cardiovascular complications. Nuclear receptors play key roles in the (patho)physiological adaptation to alterations in energy status.

During the past few years, our research focused on the role of the fatty acid and fibrate-activated PPARs and the bile acid-activated nuclear receptors FXR and TGR5 in the regulation of lipid and glucose metabolism and energy homeostasis.

To obtain further insights in the regulatory role of nuclear receptors in metabolism and energy homeostasis, studies using animal models of the nuclear receptors are performed, together with molecular approaches to unravel the molecular mechanisms, combined with the study of pharmacological ligands and translational studies in human cohorts. These approaches will uncover new therapeutic strategies for the treatment of metabolic diseases such as type 2 diabetes and dyslipidemia.

Highlights

  • ERC Advanced Grant “Bile acid, immune-metabolism, lipid and glucose homeostasis”

  • Fondation LEDUCQ: “Transatlantic Network of Excellence in Cardiovascula Diseasesr: Defining and targeting epigenetic pathways in monocytes and macrophages that contribute to cardiovascular disease”

  • RHU PRECINASH : “Non-alcoholic steato-hepatitis from disease stratification to novel therapeutic approaches”

  • Labex EGID

Transversal projects

“NASH, Pathophysiologie and Therapeutic Interventions”

NAFLD is the liver phenotype of the metabolic syndrome, for which treatment options are lacking and its diagnosis by biopsy is not optimal. Thus, there is an urgent need to identify molecular signatures and markers of obesity-driven NASH and the response to treatment. We aim to identify networks associated with NAFLD and to discover potential biomarkers and therapeutic targets for NASH treatment by performing 1/ translational studies on human cohorts of NAFLD; 2/ preclinical studies in murine model of NAFLD; 3/ mechanistic and pharmacological studies on PPAR functions in the liver (RHU Precinash).

“Bile Acids, FXR and Immune-Metabolism”

We study the role of bile acids, acting through the nuclear receptor Farnesoid X Receptor (FXR) and the G protein-coupled membrane receptor TGR5, in lipid and glucose metabolism by 1/ analysis of human tissues (liver, intestine, adipose tissue); 2/ studying the pathophysiological functions of these receptors in metabolic tissues using organ-specific FXR-deficient mice; 3/ mechanistic in vitro approaches; 4/ pharmacological studies (ERC Advanced grant).

Mitochondria, cardiac function and cardioprotection”

Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. Patients suffering from CHD face myocardial ischemia-reperfusion injury, not only when they experience an acute myocardial infarction, but also during the cardiopulmonary bypass required for coronary artery by-pass graft surgery (CABG). Preventing cardiomyocyte death after ischemia-reperfusion is still a first-line unmet clinical need. We hypothesize that poor cardiac mitochondrial function, as encountered in diabetic and old patients, is responsible for poor myocardial function and IR tolerance. We thus anticipate that boosting cardiac mitochondrial function by interfering with nuclear receptor signaling is a relevant pharmacological target in these patients. Our translational research project ranges from clinical trial to human myocardial sample exploration and molecular biology and is designed to bring evidence and relevant approaches to improve patient care (IHU Precidiab).

Membres

Bart STAELS
PU-PH, group leader
ORCID number : 0000-0002-3784-1503

Kadiombo BANTUBUNGI
MCU

Olivier BRIAND
MCU

Sandrine CARON
MCU

Augustin COISNE
MCU-PH

Delphine EBERLE
MCU

François PONTANA
MCU-PH

Joël HAAS
CR Inserm

Audrey HELLEBOID
MCU

Fanny LALLOYER
MCU

Sophie LESTAVEL
PU

David MONTAIGNE
PU-PH

Anne MUHR-TAILLEUX
PU

Réjane PAUMELLE-LESTRELIN
PU

Gao VANCE
Post-doc

Laura BUTRUILLE
Post-doc

Sarah DUCASTEL
Post-doc

Kévin ORY
Post-doc

Emmanuelle VALLEZ
Engineer, technician, IPL

Eric BAUGE
Engineer, technician, IPL

Bruno DERUDAS
Engineer, technician, IPL

Emilie DORCHIES
Engineer, technician, IPL

Isabelle DUPLAN-COQUELLE
Engineer, technician, Univ

Pauline JACQUEMAIN
Engineer, technician, CDD Univ

Xavier MARECHAL
Engineer, technician, Univ

Emilie NICOLAS
Engineer, technician, CDD Univ

Charlène POURPE
Engineer, technician, Univ

Véronique TOUCHE
Engineer, technician, Univ

Eloïse WOITRAIN
Engineer, technician, CDD Ass. privée

Simon PESCHARD
PhD student

Lucie BERNARD
PhD student

Ludivine CLAVREUL
PhD student

Benjamin DECKMYN
PhD student

Raphaël DECOIN
PhD student

Audrey DEPRINCE
PhD student

Guillaume GRZYCH
PhD student

Doriane HENRY
PhD student

Margaux NAWROT
PhD student

Sandro NINNI
PhD student

Arielle NZOUSSI-LOUBOTA
PhD student

Staniel ORTMANS
PhD student

Kubra OZKAN
Master 2 student

Matéo ANDRIEU
Master 2 student

Chloé BLONDEL
Master 2 student

Nadia ESSONGHE
Master 2 student

Elena DURAN-GONZALEZ
Master 2 student

Viktor LIENARD
Master 2 student

Publications

Montaigne D., Marechal X., Coisne A., Debry N., Modine T., Fayad G., Potelle C., El Arid JM., Mouton S., Sebti Y., Duez H., Preau S., Remy-Jouet I., Zerimech F., Koussa M., Richard V., Nevière R., Edme JL., Lefebvre P., Staels B.
Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients.
Circulation 2014;130(7):554-64.

Trabelsi M.S., Daoudi M., Prawitt J., Ducastel S., Touche V., Sayin S.I., …, Staels B.*, Lestavel S.
Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.
Nat Commun 2015;6:7629.

Briand O., Touche V., Colin S., Brufau G., Davalos A., Schonewille M., Bovenga F., Carriere V., de Boer J.F., Dugardin C., Riveau B., Clavey V., Tailleux A., Moschetta A., Lasuncion M.A., Groen A.K., Staels B.*, Lestavel S.
Liver X receptor regulates triglyceride absorption through intestinal down-regulation of scavenger receptor class B, type 1.
Gastroenterology 2016 150:650-8.

D. Montaigne, X. Marechal, T. Modine, A. Coisne, S. Mouton, G. Fayad, S. Ninni, C. Klein, S. Ortmans, C. Seunes, C. Potelle, A. Berthier, C. Gheeraert, C. Piveteau, R. Deprez, J. Eeckhoute, H. Duez, D. Lacroix, B. Deprez, B. Jegou, M. Koussa, J.L. Edme, P. Lefebvre, B. Staels.
Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-erba antagonism: a single-centre propensity-matched cohort study and a randomised study.
The Lancet, 2018, 391, 59-69.

Paumelle R., Haas J.T., Hennuyer N., Bauge E., Deleye Y., Mesotten D., Langouche L., Vanhoutte J., Cudejko C., Wouters K., Hannou S.A., Legry V., Lancel S., Lalloyer F., Polizzi A., Smati S., Gourdy P., Vallez E., Bouchaert E., Derudas B., Dehondt H., Gheeraert C., Fleury S., Tailleux A., Montagner A., Wahli W., Van den Berghe G., Guillou H., Dombrowicz D., Staels B.
Hepatic PPARα is critical in the metabolic adaptation to sepsis.
J. Hepatol., 2019 ; 70, 963-973.


Keywords

Physiology ; Métabolism and nutrition ; Metabolic disorders ; Nuclear receptors

Team contact

Bart Staels
PU-PH, group leader

bart.staels@pasteur-lille.fr