RT Journal Article
T1 Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
A1 Wculek, Stefanie K.
A1 Fernández-Bravo, Sergio
A1 Torres-Ruiz, Raúl
A1 Gomez-Sánchez, Maria José
A1 Hernández-Walias, José Carlos
A1 Moraes Ferreira, Frederico
A1 Corraliza, Ana María
A1 Sancho, David
A1 Esteban, Vanesa
A1 Rodriguez-Perales, Sandra
A1 Nakaya, Helder I.
A1 Salas, Azucena
A1 Campos-Martín, Yolanda
A1 Martínez-Zamorano, Elena
A1 Muñoz-López, Diego
A1 Blumberg, Richard S.
A1 Martín Adrados, Beatriz
A1 Valle Noguera, Ana
A1 Cruz Adalia, Aranzazu
A1 Olivares Olivares, Bernardo David
A1 Gómez Del Moral Martín-Consuegra, Manuel María
A1 Cubero Palero, Francisco Javier
A1 Martínez Naves, Eduardo
AB 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.
PB Frontiers Media
SN 1664-3224
YR 2023
FD 2023-06-30
LK https://hdl.handle.net/20.500.14352/91882
UL https://hdl.handle.net/20.500.14352/91882
LA eng
DS Docta Complutense
RD 30 sept 2024