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Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during UC
  1. Guillaume Bouguen1,2,3,4,5,
  2. Audrey Langlois1,2,
  3. Madjid Djouina1,2,
  4. Julien Branche1,6,
  5. Dine Koriche1,7,
  6. Edmone Dewaeles1,2,
  7. Alice Mongy1,2,
  8. Johan Auwerx8,9,
  9. Jean-Frederic Colombel1,2,6,10,
  10. Pierre Desreumaux1,2,6,
  11. Laurent Dubuquoy1,2,
  12. Benjamin Bertin1,2,11
  1. 1Université Lille Nord de France, Lille, France
  2. 2Inserm U995, Lille, France
  3. 3Service des Maladies de l'Appareil digestif, University Hospital of Rennes, Pontchaillou, France
  4. 4Inserm, UMR991, Liver Metabolism and Cancer, Rennes, France
  5. 5Université de Rennes 1, Rennes, France
  6. 6CHU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Claude Huriez, Lille, France
  7. 7CHU Lille, Service de Chirurgie Digestive et Transplantations, Hôpital Claude Huriez, Lille, France
  8. 8Institut Clinique de la souris, Illkirch, France
  9. 9Laboratory of Integrative and Systems Physiology, Ecole polytechnique fédérale de Lausanne, Lausanne, Switzerland
  10. 10Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA
  11. 11UDSL, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France
  1. Correspondence to Dr Benjamin Bertin, Inserm U995, Amphi J&K, Boulevard du Prof. Jules Leclercq, Lille cedex 59045, France; benjamin.bertin-2{at}


Background and aims 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.


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