title: Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice.
abstract: OBJECTIVE
  Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation.
  
  
  METHODS
  By using a combination of primary cell culture, pharmacological experiments, mice deficient for the Gr specifically in macrophages and transgenic mice overexpressing Gilz in macrophages, we explored the involvement of the Gr-Gilz axis in KC in the pathophysiology of obesity-induced liver inflammation.
  
  
  RESULTS
  Obesity was associated with a downregulation of the Gr and Gilz, and an impairment of Gilz induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of Gilz expression in isolated KC transfected with Gilz siRNA demonstrated that Gilz downregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obese transgenic mice specifically overexpressing Gilz in macrophages. Pharmacological inhibition of the Gr showed that impairment of Gilz induction in KC by LPS and DEX in obesity was driven by a downregulation of the Gr. In mice specifically deficient for Gr in macrophages, Gilz expression was low, leading to an exacerbation of obesity-induced liver inflammation.
  
  
  CONCLUSIONS
  Obesity is associated with a downregulation of the Gr-Gilz axis in KC, which promotes liver inflammation. The Gr-Gilz axis in KC is an important target for the regulation of liver inflammation in obesity.
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Robert
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Hédia
authors.initials: H
authors.lastname: Boujedidi
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bigorgne
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Gladys
authors.initials: G
authors.lastname: Ferrere
authors.affiliation: AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France.
authors.forename: Cosmin Sebastian
authors.initials: CS
authors.lastname: Voican
authors.affiliation: Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Vettorazzi
authors.affiliation: Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany.
authors.forename: Jan Peter
authors.initials: JP
authors.lastname: Tuckermann
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouchet-Delbos
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France.
authors.forename: Thi
authors.initials: T
authors.lastname: Tran
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Hemon
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Puchois
authors.affiliation: Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service de chirurgie minimale invasive, DHU Hépatinov, Clamart, France.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Dagher
authors.affiliation: AP-HP, Hôpital Européen Georges Pompidou, Service de chirurgie, Paris, France; AP-HP, Hôpital Avicenne, Service de chirurgie, Bobigny, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Douard
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; IFR 141 Institut Paris-Sud d'Innovation Thérapeutique, Châtenay-Malabry, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Gaudin
authors.affiliation: IFR 141 Institut Paris-Sud d'Innovation Thérapeutique, Châtenay-Malabry, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Gary-Gouy
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Capel
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Durand-Gasselin
authors.affiliation: AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Prévot
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rousset
authors.affiliation: AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Naveau
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Godot
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
authors.affiliation: Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; INSERM, U693, Le Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, France; AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et Maladies de la Reproduction, Le Kremlin-Bicêtre, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France. Electronic address: gabriel.perlemuter@aphp.fr.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Perlemuter
authors.affiliation: INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France. Electronic address: cassard.doulcier@u-psud.fr.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cassard
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D006505:Hepatitis / Q000209:etiology*; D007728:Kupffer Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C498608:Dsip1 protein, mouse; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D003907:Dexamethasone
keywords: Glucocorticoid receptor; Glucocorticoid-induced leucine zipper; Inflammation; Kupffer cells; Liver; Obesity