title: Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis.
abstract: OBJECTIVE
  Immune tolerance breakdown during UC involves the peroxisome proliferator-activated receptor-γ (PPARγ), a key factor in mucosal homoeostasis and the therapeutic target of 5-aminosalycilates, which expression is impaired during UC. Here we assess the impact of glucocorticoids (GCs) on PPARγ expression, focusing especially on extra-adrenal cortisol production by colonic epithelial cells (CECs).
  
  
  METHODS
  Activation of PPARγ in the colon was evaluated using transgenic mice for the luciferase gene under PPAR control (peroxisome proliferator response element-luciferase mice). Protein and mRNA expression of PPARγ were evaluated with colon fragments and purified CEC from mice. Cortisol production and steroidogenic factor expression were quantified in human CEC of patients with UC and those of controls. Gene expression knockdown by short hairpin RNA in Caco-2 cells was used for functional studies.
  
  
  RESULTS
  GCs were able to raise luciferase activity in peroxisome proliferator response element-luciferase mice. In the mice colons and Caco-2 cells, PPARγ expression was increased either with GCs or with an inducer of steroidogenesis and then decreased after treatment with a steroidogenesis inhibitor. Cortisol production and steroidogenic factor expression, such as liver receptor homologue-1 (LRH-1), were decreased in CEC isolated from patients with UC, directly correlating with PPARγ impairment. Experiments on Caco-2 cells lacking LRH-1 expression confirmed that LRH-1 controls PPARγ expression by regulating GC synthesis in CEC.
  
  
  CONCLUSIONS
  These results demonstrate cortisol control of PPARγ expression in CEC, highlighting cortisol production deficiency in colonocytes as a key molecular event in the pathophysiology of UC.
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France Service des Maladies de l'Appareil digestif, University Hospital of Rennes, Pontchaillou, France Inserm, UMR991, Liver Metabolism and Cancer, Rennes, France Université de Rennes 1, Rennes, France.
authors: Guillaume
authors: G
authors: Bouguen
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France.
authors: Audrey
authors: A
authors: Langlois
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France.
authors: Madjid
authors: M
authors: Djouina
authors: Université Lille Nord de France, Lille, France CHU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Claude Huriez, Lille, France.
authors: Julien
authors: J
authors: Branche
authors: Université Lille Nord de France, Lille, France CHU Lille, Service de Chirurgie Digestive et Transplantations, Hôpital Claude Huriez, Lille, France.
authors: Dine
authors: D
authors: Koriche
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France.
authors: Edmone
authors: E
authors: Dewaeles
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France.
authors: Alice
authors: A
authors: Mongy
authors: Institut Clinique de la souris, Illkirch, France Laboratory of Integrative and Systems Physiology, Ecole polytechnique fédérale de Lausanne, Lausanne, Switzerland.
authors: Johan
authors: J
authors: Auwerx
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France CHU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Claude Huriez, Lille, France Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA.
authors: Jean-Frederic
authors: JF
authors: Colombel
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France CHU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Claude Huriez, Lille, France.
authors: Pierre
authors: P
authors: Desreumaux
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France.
authors: Laurent
authors: L
authors: Dubuquoy
authors: Université Lille Nord de France, Lille, France Inserm U995, Lille, France UDSL, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
authors: Benjamin
authors: B
authors: Bertin
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000096:biosynthesis*; D006801:Humans; D007108:Immune Tolerance; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; C431936:Nr5a2 protein, mouse; D047495:PPAR gamma; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear
keywords: BASIC SCIENCES; INTESTINAL EPITHELIUM; MOLECULAR BIOLOGY; SIGNALING; ULCERATIVE COLITIS