RT Journal Article SR Electronic T1 Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 901 OP 910 DO 10.1136/gutjnl-2014-307618 VO 64 IS 6 A1 Guillaume Bouguen A1 Audrey Langlois A1 Madjid Djouina A1 Julien Branche A1 Dine Koriche A1 Edmone Dewaeles A1 Alice Mongy A1 Johan Auwerx A1 Jean-Frederic Colombel A1 Pierre Desreumaux A1 Laurent Dubuquoy A1 Benjamin Bertin YR 2015 UL http://gut.bmj.com/content/64/6/901.abstract AB 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.