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Metabolic Diseases, Diabetes and co-morbidities

The increased incidence of diabetes and obesity worldwide has greatly augmented the risk for numerous associated co-morbidities such as Non Alcoholic Fatty Liver Diseases (NAFLD), cardiovascular (CVD) and chronic kidney disease (CKD) that lead to reduced quality of life and increased mortality. The objectives of our team are to decipher the underlying mechanisms leading to co-morbidities induced by metabolic disorders with an emphasis on metabolic liver diseases and cardiorenal complications.

Type 2 diabetes and NAFLD
Type 2 diabetes (T2D) and Nonalcoholic fatty liver disease (NAFLD) are increasing worldwide owing to the obesity pandemic. Obesity and insulin resistance are key pathogenic factors associated with the presence of T2D and NAFLD. As a consequence, NAFLD is very common among T2D individuals. It is estimated that up to 90% of T2D patients develop NAFLD. In T2D patients developing NAFLD, the prevalence of NASH could reach 80% with a prevalence of moderate to severe fibrosis estimated to 22-60%. The relationship between NAFLD and T2D is strong and complex and it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of T2D. Our objectives are to understand the mechanisms by which T2D promotes NAFLD and vice versa. We are particularly interested in: (i) the roles of sphingolipids and ER stress on hepatic insulin resistance and progression to NASH, (ii) the relationship between NAFLD, DT2 and bone metabolism through the RANK receptor, (iii) the metabolism of hepatic stellate cells responsible for fibrogenesis. These studies are carried out on rodent or human primary cultures, on genetically modified animals but also through translational studies in humans thanks to the clinicians of the team.

 

Metabolic co-morbidities group
Our aim is to improve the understanding of the pathophysiological roles and signaling pathways whereby mineralocorticoid receptor (MR) promotes pathologies in various organs. Our work combines cellular and molecular approaches, animal physiology, pharmacological studies and includes translational research aimed to identify and validate biomarkers of Mineralocorticoid Receptor activation in various diseases and novel therapeutic use of MR antagonists.

The current project is centred on comorbidities as consequences or origin of metabolic diseases, considering mineralocorticoid receptor antagonism (MRA) as a potential therapeutic strategy in this context. We propose that the activation of the mineralocorticoid receptor (MR) is a common underlying mechanism and a therapeutic target in several comorbidities.

 

 

Team leader : Dr Fabienne FOUFELLE (DR; Inserm)

Deputy : Dr Frédéric JAISSER (DR; Inserm)

 

Team Members:

Researchers:  Olivier BOURRON (MCU-PH; Sorbonne Univ),  Jean Michel DAVAINE (PH; AP-HP), Eric HAJDUCH (CR; Inserm), Agnès HARTEMANN (PU-PH; Sorbonne Univ), Marie LAGOUGE (CR; CNRS),  Nicolette FARMAN (DR em; Inserm), Pascal FERRE (PU-PH, Sorbonne Univ), Pr Vlad RATZIU (PU-PH; Sorbonne Univ), Pr Jérome TOURRET (MCU-PH; Sorbonne Univ). 

Technical Staff: Sophie TAN (IE; Sorbonne Univ), Aurore BADIA-MADEBA (AI; Inserm), Nabiha BOUJARDINE (AI, Univ Paris Descartes), Kamel MELLIANI (Adj Tec; Inserm).

Young Researchers: Cécile BANDET (Post-Doc; Sorbonne Univ), Benjamin BONNARD (PhD Student; Sorbonne Univ), Floriane LACHKAR (PhD Student; Sorbonne Univ), Lionel LATTENIST (Post-Doc; Inserm), Clara LEFRANC (PhD Student; Inserm), Van Tuan NGUYEN (Post-Doc; Inserm) Roberto PALACIOS (Post-Doc; Inserm), Franck PHAN (PhD Student; Inserm), Kohei UEDA (Post-Doc; Inserm).

Students:  Arnaud DANCE (Master Student; Univ Paris Saclay), Paul GABARE (Master Student; Univ Paris Sud), Marie GENTY (Master Student; Sorbonne Univ), Heloise GIUDICELLI (Master Student; Univ Paris Descartes), Qui Trung NGO ( Master Student; Sorbonne Univ), Lucile OUVRY(Master Student; Sorbonne Univ), Barbora VALENTOVA (Erasmus Student). 

Administration : Valérie RESVE (Tec; Inserm)

Contact details: 33 (0)1 44 27 24 31,  Email

 

Publications :

  • Barrera-Chimal J, Estrela GR, Lechner SM, Giraud S, El Moghrabi S, Kaaki S, Kolkhof P, Hauet T, Jaisser F. The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling. Kidney Int. 2018 Jun;93(6):1344-1355.
  • Pais R, Redheuil A, Cluzel P, Ratziu V, Giral P. Relationship between fatty liver, specific and multiple-site atherosclerosis and 10-year Framingham Score. Hepatology. 2018 Aug 19.
  • Bandet CL, Mahfouz R, Véret J, Sotiropoulos A, Poirier M, Giussani P, Campana M, Philippe E, Blachnio-Zabielska A, Ballaire R, Le Liepvre X, Bourron O, Berkeš D, Górski J, Ferré P, Le Stunff H, Foufelle F, Hajduch E. Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions. Diabetes. 2018 Jul;67(7):1258-1271.
  • Szpigel A, Hainault I, Carlier A, Venteclef N, Batto AF, Hajduch E, Bernard C, Ktorza A, Gautier JF, Ferré P, Bourron O, Foufelle F. Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes. Diabetologia. 2018 Feb;61(2):399-412.
  • Martínez-Martínez E, Buonafine M, Boukhalfa I, Ibarrola J, Fernández-Celis A, Kolkhof P, Rossignol P, Girerd N, Mulder P, López-Andrés N, Ouvrard-Pascaud A, Jaisser F. Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NFκB Pathway. Hypertension. 2017 Dec;70(6):1148-1156.
  • Lattenist L, Lechner SM, Messaoudi S, Le Mercier A, El Moghrabi S, Prince S, Bobadilla NA, Kolkhof P, Jaisser F, Barrera-Chimal J. Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury-Mediated Chronic Kidney Disease: Role of Oxidative Stress. Hypertension. 2017 May; 69(5):870-878.
  • Barrera-Chimal J, André-Grégoire G, Nguyen Dinh Cat A, Lechner SM, Cau J, Prince S, Kolkhof P, Loirand G, Sauzeau V, Hauet T, Jaisser F. Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1. J Am Soc Nephrol. 2017, (4):1216-1226.
  • Baiceanu A, Mesdom P, Lagouge M, Foufelle F. Endoplasmic reticulum proteostasis in hepatic steatosis. Nat Rev Endocrinol. 2016 Dec;12(12):710-722.
  • Amador CA, Bertocchio JP, Andre-Gregoire G, Placier S, Duong Van Huyen JP, El Moghrabi S, Berger S, Warnock DG, Chatziantoniou C, Jaffe IZ, Rieu P, Jaisser F. Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration. Kidney Int. 2016 Feb;89(2):354-62.
  • Urbanet R, Nguyen Dinh Cat A, Feraco A, Venteclef N, El Mogrhabi S, Sierra-Ramos C, Alvarez de la Rosa D, Adler GK, Quilliot D, Rossignol P, Fallo F, Touyz RM, Jaisser F. Adipocyte mineralocorticoid receptor activation leads to metabolic syndrome and induction of Prostaglandin D2 Synthase. Hypertension. 2015, Jul;66(1):149-57
  • Bourron O, Caron-Debarle M, Hie M, Amoura Z, Andreelli F, Halbron M, Fonfrede M, Leroux G, Vigouroux C, Hartemann A. Type B Insulin-resistance syndrome: a cause of reversible autoimmune hypoglycaemia. Lancet. 2014, Oct 25;384(9953):1548.


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