Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis
| Autor: | Glauben Landskron, Karen Dubois-Camacho, Octavio Orellana-Serradell, Marjorie De la Fuente, Daniela Parada-Venegas, Mirit Bitrán, David Diaz-Jimenez, Shuang Tang, John A. Cidlowski, Xiaoling Li, Hector Molina, Carlos M. Gonzalez, Daniela Simian, Jaime Lubascher, Victor Pola, Martín Montecino, Tjasso Blokzijl, Klaas Nico Faber, María-Julieta González, Rodrigo Quera, Marcela A. Hermoso |
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| Přispěvatelé: | Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
EXPRESSION
MECHANISM BETA General Medicine CANCER LRH-1 glucocorticoid receptor ulcerative colitis steroid refractoriness steroid dependency Intestines Mice COLON ORGANOIDS MANAGEMENT Animals Humans Colitis Ulcerative Steroids Intestinal Mucosa NUCLEAR RECEPTOR LRH-1 Glucocorticoids RESISTANCE INFLAMMATORY-BOWEL-DISEASE |
| Zdroj: | Cells; Volume 11; Issue 12; Pages: 1905 Cells, 11(12):1905. MDPI AG |
| ISSN: | 2073-4409 |
| Popis: | 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 (GRiKO) 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. |
| Databáze: | OpenAIRE |
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