Examinando por Autor "Cidlowski, John A"

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    Regulation of the intestinal extra-adrenal steroidogenic pathway component LRH-1 by glucocorticoids in ulcerative colitis
    (MDPI, 2022-06-12) Landskron, Glauben; Dubois-Camacho, Karen; Orellana-Serradell, Octavio; De la Fuente, Marjorie; Parada-Venegas, Daniela; Bitrán, Mirit; Díaz-Jiménez, David; Tang, Shuang; Cidlowski, John A; Li, Xiaoling; Molina, Héctor; González, Carlos M; Simian, Daniela; Lubascher, Jaime; Pola, Victor; Montecino, Martín; Blokzijl, Tjasso; Faber, Klaas Nico; González, María-Julieta; Quera, Rodrigo; Hermoso, Marcela A
    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.