LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease.
Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocyte-dependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, Illkirch, and Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Agnes
A
Coste
Laurent
L
Dubuquoy
Romain
R
Barnouin
Jean-Sebastien
JS
Annicotte
Benjamin
B
Magnier
Mario
M
Notti
Nadia
N
Corazza
Maria Cristina
MC
Antal
Daniel
D
Metzger
Pierre
P
Desreumaux
Thomas
T
Brunner
Johan
J
Auwerx
Kristina
K
Schoonjans
D000328:Adult; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D003345:Corticosterone / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology*; D020895:Enterocytes / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000096:biosynthesis*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C082631:NR5A2 protein, human; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003345:Corticosterone