Regulation of the intestinal extra-adrenal steroidogenic pathway component LRH-1 by glucocorticoids in ulcerative colitis

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dc.contributor.authorLandskron, Glauben
dc.contributor.authorDubois-Camacho, Karen
dc.contributor.authorOrellana-Serradell, Octavio
dc.contributor.authorDe la Fuente, Marjorie
dc.contributor.authorParada-Venegas, Daniela
dc.contributor.authorBitrán, Mirit
dc.contributor.authorDíaz-Jiménez, David
dc.contributor.authorTang, Shuang
dc.contributor.authorCidlowski, John A
dc.contributor.authorLi, Xiaoling
dc.contributor.authorMolina, Héctor
dc.contributor.authorGonzález, Carlos M
dc.contributor.authorSimian, Daniela
dc.contributor.authorLubascher, Jaime
dc.contributor.authorPola, Victor
dc.contributor.authorMontecino, Martín
dc.contributor.authorBlokzijl, Tjasso
dc.contributor.authorFaber, Klaas Nico
dc.contributor.authorGonzález, María-Julieta
dc.contributor.authorQuera, Rodrigo
dc.contributor.authorHermoso, Marcela A
dc.date.accessioned2022-11-03T13:18:37Z
dc.date.available2022-11-03T13:18:37Z
dc.date.issued2022-06-12
dc.description.abstractUlcerative 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.en
dc.description.sponsorshipThis 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.citationCells, Vol. 11, N°12, Art. 1905, (2022) p. 1-20.en
dc.identifier.doihttps://doi.org/10.3390/cells11121905
dc.identifier.issn2073-4409
dc.identifier.orcidhttps://orcid.org/0000-0002-7953-6769
dc.identifier.urihttp://hdl.handle.net/20.500.12254/2589
dc.language.isoenen
dc.publisherMDPI
dc.rightsAtribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/cl/
dc.subject.otherGlucocorticoid receptoren
dc.subject.otherUlcerative colitisen
dc.subject.otherSteroid refractorinessen
dc.subject.otherSteroid dependencyen
dc.titleRegulation of the intestinal extra-adrenal steroidogenic pathway component LRH-1 by glucocorticoids in ulcerative colitisen
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