{"doi":"10.3390/cells11121905","title":"Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis","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.","journal":"Cells","year":2022,"id":271813,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9441,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":937221,"name":"Karen Dubois‐Camacho","orcid":"0000-0002-2048-4474","position":1,"is_corresponding":false},{"id":937222,"name":"Octavio Orellana‐Serradell","orcid":"0000-0002-9390-0758","position":2,"is_corresponding":false},{"id":937223,"name":"Marjorie De la Fuente","orcid":"0000-0003-0577-7604","position":3,"is_corresponding":false},{"id":937640,"name":"Daniela Parada‐Venegas","orcid":null,"position":4,"is_corresponding":false},{"id":937641,"name":"Mirit Bitrán","orcid":null,"position":5,"is_corresponding":false},{"id":476217,"name":"David Díaz-Jiménez","orcid":null,"position":6,"is_corresponding":false},{"id":443897,"name":"Shuang Tang","orcid":"0000-0002-3501-7836","position":7,"is_corresponding":false},{"id":267572,"name":"John A. Cidlowski","orcid":"0000-0003-1420-0516","position":8,"is_corresponding":false},{"id":241287,"name":"Xiaoling Li","orcid":"0000-0001-5920-7784","position":9,"is_corresponding":false},{"id":937642,"name":"Hector Molina","orcid":null,"position":10,"is_corresponding":false},{"id":937224,"name":"Carlos González","orcid":"0000-0002-7639-0434","position":11,"is_corresponding":false},{"id":937225,"name":"Daniela Simian","orcid":"0000-0002-5309-1503","position":12,"is_corresponding":false},{"id":937643,"name":"Jaime Lubascher","orcid":null,"position":13,"is_corresponding":false},{"id":937226,"name":"Víctor Pola","orcid":"0000-0002-3156-5130","position":14,"is_corresponding":false},{"id":430943,"name":"Martı́n Montecino","orcid":"0000-0002-6025-0023","position":15,"is_corresponding":false},{"id":937227,"name":"Tjasso Blokzijl","orcid":"0000-0003-3351-7092","position":16,"is_corresponding":false},{"id":937228,"name":"Klaas Nico Faber","orcid":"0000-0001-8893-3312","position":17,"is_corresponding":false},{"id":937229,"name":"María‐Julieta González","orcid":"0000-0002-7513-3444","position":18,"is_corresponding":false},{"id":937230,"name":"Rodrigo Quera","orcid":"0000-0001-5854-0526","position":19,"is_corresponding":false},{"id":475276,"name":"Marcela A. 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