Regulation of the intestinal extra-adrenal steroidogenic pathway component LRH-1 by glucocorticoids in ulcerative colitis
dc.contributor.author | Landskron, Glauben | |
dc.contributor.author | Dubois-Camacho, Karen | |
dc.contributor.author | Orellana-Serradell, Octavio | |
dc.contributor.author | De la Fuente, Marjorie | |
dc.contributor.author | Parada-Venegas, Daniela | |
dc.contributor.author | Bitrán, Mirit | |
dc.contributor.author | Díaz-Jiménez, David | |
dc.contributor.author | Tang, Shuang | |
dc.contributor.author | Cidlowski, John A | |
dc.contributor.author | Li, Xiaoling | |
dc.contributor.author | Molina, Héctor | |
dc.contributor.author | González, Carlos M | |
dc.contributor.author | Simian, Daniela | |
dc.contributor.author | Lubascher, Jaime | |
dc.contributor.author | Pola, Victor | |
dc.contributor.author | Montecino, Martín | |
dc.contributor.author | Blokzijl, Tjasso | |
dc.contributor.author | Faber, Klaas Nico | |
dc.contributor.author | González, María-Julieta | |
dc.contributor.author | Quera, Rodrigo | |
dc.contributor.author | Hermoso, Marcela A | |
dc.date.accessioned | 2022-11-03T13:18:37Z | |
dc.date.available | 2022-11-03T13:18:37Z | |
dc.date.issued | 2022-06-12 | |
dc.description.abstract | 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. | es |
dc.description.sponsorship | This research was funded by the National Agency of Research and Development ANID/FONDECYT GRANTS 1170648, 1220702 (M.A.H.), 11190990 (M.D.l.F.), 3190931 (G.L.), 3210367 (K.D.-C.), Proyecto Puente ICBM2021_ 570333 (M.A.H.); ANID/FONDAP15090007 (M.M.), Glucocorticoid hormone action 1ZIA ES090057 24; Apoptosis 1ZIA ES090079 24; Molecular genetics support to identify gene/environment interactions in disease 1ZIC ES102546 12 (J.A.C.); Intramural Research Program of National Institute of Environmental Health Sciences of the NIH (X.L.) (Z01 ES102205) and a scholarship from the Vice-Rector’s Office for Academic Affairs, Postgraduate and Postgraduate Department, Universidad de Chile (M.B.). | es |
dc.identifier.citation | Cells. 2022 Jun 12;11(12):1905. doi: 10.3390/cells11121905. | es |
dc.identifier.issn | 2073-4409 | |
dc.identifier.orcid | https://orcid.org/0000-0002-7953-6769 | es |
dc.identifier.orcid | https://doi.org/10.3390/cells11121905 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12254/2589 | |
dc.language.iso | en_US | es |
dc.publisher | MDPI | es |
dc.relation.ispartofseries | Cells;11 | |
dc.rights | Atribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL) | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/3.0/cl/ | |
dc.subject.other | Glucocorticoid receptor | es |
dc.subject.other | Ulcerative colitis | es |
dc.subject.other | Steroid refractoriness | es |
dc.subject.other | Steroid dependency | es |
dc.title | Regulation of the intestinal extra-adrenal steroidogenic pathway component LRH-1 by glucocorticoids in ulcerative colitis | es |
dc.type | Artículo | es |
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