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 Quera; Marcela A. Hermoso

doi:10.3390/cells11121905

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

Clínica Universidad de los Andes

Research output: Contribution to journal › Article › peer-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 (GR^iKO) 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 language	English
Article number	1905
Journal	Cells
Volume	11
Issue number	12
DOIs	https://doi.org/10.3390/cells11121905
State	Published - 12 Jun 2022

Bibliographical note

Funding Information:
Funding: This research was funded by the National Agency of Research and Development ANID/ FONDECYT GRANTS 1170648 (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.).

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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10.3390/cells11121905

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Landskron, G., Dubois-Camacho, K., Orellana-Serradell, O., De la Fuente, M., Parada-Venegas, D., Bitrán, M., Diaz-Jimenez, D., Tang, S., Cidlowski, J. A., Li, X., Molina, H., Gonzalez, C. M., Simian, D., Lubascher, J., Pola, V., Montecino, M., Blokzijl, T., Faber, K. N., González, M. J., ... Hermoso, M. A. (2022). Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis. Cells, 11(12), Article 1905. https://doi.org/10.3390/cells11121905

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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.",

keywords = "Animals, Colitis, Ulcerative/drug therapy, Glucocorticoids/metabolism, Humans, Intestinal Mucosa/metabolism, Intestines, Mice, Steroids/metabolism",

author = "Glauben Landskron and Karen Dubois-Camacho and Octavio Orellana-Serradell and {De la Fuente}, Marjorie and Daniela Parada-Venegas and Mirit Bitr{\'a}n and David Diaz-Jimenez and Shuang Tang and Cidlowski, {John A.} and Xiaoling Li and Hector Molina and Gonzalez, {Carlos M.} and Daniela Simian and Jaime Lubascher and Victor Pola and Mart{\'i}n Montecino and Tjasso Blokzijl and Faber, {Klaas Nico} and Gonz{\'a}lez, {Mar{\'i}a Julieta} and Rodrigo Quera and Hermoso, {Marcela A.}",

note = "Funding Information: Funding: This research was funded by the National Agency of Research and Development ANID/ FONDECYT GRANTS 1170648 (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{\textquoteright}s Office for Academic Affairs, Postgraduate and Postgraduate Department, Universidad de Chile (M.B.). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jun,

day = "12",

doi = "10.3390/cells11121905",

language = "English",

volume = "11",

journal = "Cells",

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Landskron, G, Dubois-Camacho, K, Orellana-Serradell, O, De la Fuente, M, Parada-Venegas, D, Bitrán, M, Diaz-Jimenez, D, Tang, S, Cidlowski, JA, Li, X, Molina, H, Gonzalez, CM, Simian, D, Lubascher, J, Pola, V, Montecino, M, Blokzijl, T, Faber, KN, González, MJ, Quera, R & Hermoso, MA 2022, 'Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis', Cells, vol. 11, no. 12, 1905. https://doi.org/10.3390/cells11121905

TY - JOUR

T1 - Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

AU - Landskron, Glauben

AU - Dubois-Camacho, Karen

AU - Orellana-Serradell, Octavio

AU - De la Fuente, Marjorie

AU - Parada-Venegas, Daniela

AU - Bitrán, Mirit

AU - Diaz-Jimenez, David

AU - Tang, Shuang

AU - Cidlowski, John A.

AU - Li, Xiaoling

AU - Molina, Hector

AU - Gonzalez, Carlos M.

AU - Simian, Daniela

AU - Lubascher, Jaime

AU - Pola, Victor

AU - Montecino, Martín

AU - Blokzijl, Tjasso

AU - Faber, Klaas Nico

AU - González, María Julieta

AU - Quera, Rodrigo

AU - Hermoso, Marcela A.

N1 - Funding Information: Funding: This research was funded by the National Agency of Research and Development ANID/ FONDECYT GRANTS 1170648 (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.). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/6/12

Y1 - 2022/6/12

N2 - 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.

AB - 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.

KW - Animals

KW - Colitis, Ulcerative/drug therapy

KW - Glucocorticoids/metabolism

KW - Humans

KW - Intestinal Mucosa/metabolism

KW - Intestines

KW - Mice

KW - Steroids/metabolism

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AN - SCOPUS:85131713831

SN - 2073-4409

VL - 11

JO - Cells

JF - Cells

IS - 12

M1 - 1905

ER -

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

Abstract

Bibliographical note

Keywords

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