Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

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 QueraMarcela A. Hermoso*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article number1905
JournalCells
Volume11
Issue number12
DOIs
StatePublished - 12 Jun 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Animals
  • Colitis, Ulcerative/drug therapy
  • Glucocorticoids/metabolism
  • Humans
  • Intestinal Mucosa/metabolism
  • Intestines
  • Mice
  • Steroids/metabolism

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