Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress

Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory re...

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Autores: Martín-Adrados , B, Wculek , Sk, Fernández-Bravo , S, Torres-Ruiz , R, Valle-Noguera , A, Gomez-Sánchez , Mj, Hernández-Walias , Jc, Ferreira , Fm, Corraliza , Am, Sancho , D, Esteban , V, Rodriguez-Perales , S, Cruz-Adalia , A, Nakaya , Hi, Salas , A, Bernardo , D, Martínez-Zamorano , E, Muñoz-López , D, Gómez del Moral , M, Cubero , Fj, Blumberg , Rs, Martínez-Naves , E, Campos Martín, Yolanda
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Castilla-La Mancha
Repositorio:RUIdeRA. Repositorio Institucional de la UCLM
OAI Identifier:oai:ruidera.uclm.es:10578/43736
Acceso en línea:http://dx.doi.org/10.3389/fimmu.2023.1185517
https://hdl.handle.net/10578/43736
Access Level:acceso abierto
Palabra clave:ER stress
HMGCS2
Inflammation
Inflammatory bowel disease
Unfolded protein response (UPR)
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spelling Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stressMartín-Adrados , BWculek , SkFernández-Bravo , STorres-Ruiz , RValle-Noguera , AGomez-Sánchez , MjHernández-Walias , JcFerreira , FmCorraliza , AmSancho , DEsteban , VRodriguez-Perales , SCruz-Adalia , ANakaya , HiSalas , ABernardo , DMartínez-Zamorano , EMuñoz-López , DGómez del Moral , MCubero , FjBlumberg , RsMartínez-Naves , ECampos Martín, YolandaER stressHMGCS2InflammationInflammatory bowel diseaseUnfolded protein response (UPR)Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease.Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells.Results: Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines.Conclusion: We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.Frontiers Media S.A.202520252023info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://dx.doi.org/10.3389/fimmu.2023.1185517https://hdl.handle.net/10578/43736reponame:RUIdeRA. Repositorio Institucional de la UCLMinstname:Universidad de Castilla-La ManchaInglésinfo:eu-repo/semantics/openAccessoai:ruidera.uclm.es:10578/437362026-05-27T07:36:41Z
dc.title.none.fl_str_mv Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
title Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
spellingShingle Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
Martín-Adrados , B
ER stress
HMGCS2
Inflammation
Inflammatory bowel disease
Unfolded protein response (UPR)
title_short Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
title_full Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
title_fullStr Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
title_full_unstemmed Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
title_sort Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
dc.creator.none.fl_str_mv Martín-Adrados , B
Wculek , Sk
Fernández-Bravo , S
Torres-Ruiz , R
Valle-Noguera , A
Gomez-Sánchez , Mj
Hernández-Walias , Jc
Ferreira , Fm
Corraliza , Am
Sancho , D
Esteban , V
Rodriguez-Perales , S
Cruz-Adalia , A
Nakaya , Hi
Salas , A
Bernardo , D
Martínez-Zamorano , E
Muñoz-López , D
Gómez del Moral , M
Cubero , Fj
Blumberg , Rs
Martínez-Naves , E
Campos Martín, Yolanda
author Martín-Adrados , B
author_facet Martín-Adrados , B
Wculek , Sk
Fernández-Bravo , S
Torres-Ruiz , R
Valle-Noguera , A
Gomez-Sánchez , Mj
Hernández-Walias , Jc
Ferreira , Fm
Corraliza , Am
Sancho , D
Esteban , V
Rodriguez-Perales , S
Cruz-Adalia , A
Nakaya , Hi
Salas , A
Bernardo , D
Martínez-Zamorano , E
Muñoz-López , D
Gómez del Moral , M
Cubero , Fj
Blumberg , Rs
Martínez-Naves , E
Campos Martín, Yolanda
author_role author
author2 Wculek , Sk
Fernández-Bravo , S
Torres-Ruiz , R
Valle-Noguera , A
Gomez-Sánchez , Mj
Hernández-Walias , Jc
Ferreira , Fm
Corraliza , Am
Sancho , D
Esteban , V
Rodriguez-Perales , S
Cruz-Adalia , A
Nakaya , Hi
Salas , A
Bernardo , D
Martínez-Zamorano , E
Muñoz-López , D
Gómez del Moral , M
Cubero , Fj
Blumberg , Rs
Martínez-Naves , E
Campos Martín, Yolanda
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ER stress
HMGCS2
Inflammation
Inflammatory bowel disease
Unfolded protein response (UPR)
topic ER stress
HMGCS2
Inflammation
Inflammatory bowel disease
Unfolded protein response (UPR)
description Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease.Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells.Results: Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines.Conclusion: We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.
publishDate 2023
dc.date.none.fl_str_mv 2023
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://dx.doi.org/10.3389/fimmu.2023.1185517
https://hdl.handle.net/10578/43736
url http://dx.doi.org/10.3389/fimmu.2023.1185517
https://hdl.handle.net/10578/43736
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:RUIdeRA. Repositorio Institucional de la UCLM
instname:Universidad de Castilla-La Mancha
instname_str Universidad de Castilla-La Mancha
reponame_str RUIdeRA. Repositorio Institucional de la UCLM
collection RUIdeRA. Repositorio Institucional de la UCLM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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