Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

Cells

Daniela Simian¹  María-Julieta González²  Rodrigo Quera³  Tjasso Blokzijl⁴  Klaas Nico Faber⁴  Jaime Lubascher⁵  Karen Dubois-Camacho⁶  Daniela Parada-Venegas⁶  Glauben Landskron⁶  Octavio Orellana-Serradell⁶  Marcela A. Hermoso⁶  Marjorie De la Fuente⁶  Hector Molina⁶  Mirit Bitrán⁶  Victor Pola⁷  Martín Montecino⁷  Shuang Tang⁸  Xiaoling Li⁹  David Diaz-Jimenez^1,10  John A. Cidlowski^1,10  Carlos M. Gonzalez^1,11 

[1] Academic Research Unit, Clínica Las Condes, Santiago 7591018, Chile;Cell and Molecular Biology Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;Centro de Enfermedades Digestivas, Programa Enfermedad Inflamatoria Intestinal, Clínica Universidad de Los Andes, Universidad de los Andes, Santiago 7620157, Chile;Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;Inflammatory Bowel Disease Program, Gastroenterology Department, Clínica Las Condes, Santiago 7591018, Chile;Innate Immunity Laboratory, Immunology Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago 8370186, Chile;Metabolism and Nuclear Medicine Group, Fudan University Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200433, China;Metabolism, Genes, and Environment Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC 27709, USA;Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC 27709, USA;School of Veterinary Medicine, Faculty of Life Sciences, Universidad Andrés Bello, Santiago 8370251, Chile;

关键词: LRH-1;    glucocorticoid receptor;    ulcerative colitis;    steroid refractoriness;    steroid dependency;   

DOI  :  10.3390/cells11121905

来源: DOAJ

【 摘 要 】

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR^iKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.

【 授权许可】

Unknown