Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function

Objective O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipid...

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Autores: González-Rellán, María J., Parracho, Tamara, Heras, Violeta, Rodríguez, Amaia, Fondevila, Marcos F., Novoa, Eva, Lima, Natalia, Varela-Rey, Marta, Senra, Ana, Chantada-Vázquez, María D. P., Ameneiro, Cristina, Bernardo, Ganeko, Fernández-Ramos, David, Lopitz-Otsoa, Fernando, Bilbao, Jon, Guallar, Diana, Fidalgo, Miguel, Crespo García, Javier, Iruzubieta Coz, Paula
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/30394
Acceso en línea:https://hdl.handle.net/10902/30394
Access Level:acceso abierto
Palabra clave:O-GlcNAcylation
Mitochondrial dysfunction
NAFLD
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
title Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
spellingShingle Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
González-Rellán, María J.
O-GlcNAcylation
Mitochondrial dysfunction
NAFLD
title_short Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
title_full Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
title_fullStr Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
title_full_unstemmed Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
title_sort Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function
dc.creator.none.fl_str_mv González-Rellán, María J.
Parracho, Tamara
Heras, Violeta
Rodríguez, Amaia
Fondevila, Marcos F.
Novoa, Eva
Lima, Natalia
Varela-Rey, Marta
Senra, Ana
Chantada-Vázquez, María D. P.
Ameneiro, Cristina
Bernardo, Ganeko
Fernández-Ramos, David
Lopitz-Otsoa, Fernando
Bilbao, Jon
Guallar, Diana
Fidalgo, Miguel
Crespo García, Javier
Iruzubieta Coz, Paula
author González-Rellán, María J.
author_facet González-Rellán, María J.
Parracho, Tamara
Heras, Violeta
Rodríguez, Amaia
Fondevila, Marcos F.
Novoa, Eva
Lima, Natalia
Varela-Rey, Marta
Senra, Ana
Chantada-Vázquez, María D. P.
Ameneiro, Cristina
Bernardo, Ganeko
Fernández-Ramos, David
Lopitz-Otsoa, Fernando
Bilbao, Jon
Guallar, Diana
Fidalgo, Miguel
Crespo García, Javier
Iruzubieta Coz, Paula
author_role author
author2 Parracho, Tamara
Heras, Violeta
Rodríguez, Amaia
Fondevila, Marcos F.
Novoa, Eva
Lima, Natalia
Varela-Rey, Marta
Senra, Ana
Chantada-Vázquez, María D. P.
Ameneiro, Cristina
Bernardo, Ganeko
Fernández-Ramos, David
Lopitz-Otsoa, Fernando
Bilbao, Jon
Guallar, Diana
Fidalgo, Miguel
Crespo García, Javier
Iruzubieta Coz, Paula
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv O-GlcNAcylation
Mitochondrial dysfunction
NAFLD
topic O-GlcNAcylation
Mitochondrial dysfunction
NAFLD
description Objective O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD. Methods We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD. Results O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD. Conclusions These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/30394
url https://hdl.handle.net/10902/30394
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Molecular Metabolism, 2023, 75, 101776
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial functionGonzález-Rellán, María J.Parracho, TamaraHeras, VioletaRodríguez, AmaiaFondevila, Marcos F.Novoa, EvaLima, NataliaVarela-Rey, MartaSenra, AnaChantada-Vázquez, María D. P.Ameneiro, CristinaBernardo, GanekoFernández-Ramos, DavidLopitz-Otsoa, FernandoBilbao, JonGuallar, DianaFidalgo, MiguelCrespo García, JavierIruzubieta Coz, PaulaO-GlcNAcylationMitochondrial dysfunctionNAFLDObjective O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD. Methods We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD. Results O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD. Conclusions These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.ACKNOWLEDGEMENTS. This work was supported by grants from: FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (MLM-C: PID2020-117116RB-I00; CD: BFU2017-87721; ML: RTI2018e101840-B-I00; RN: PID2021-126096NB-I00 and RED2018-102379-T); Xunta de Galicia (RN: 2021-CP085 and 2020-PG0157); Fundación BBVA (to RN); Subprograma Retos Colaboración RTC2019-007125-1 (to MLM-C); Proyectos Investigación en Salud DTS20/00138 (to MLM-C); Proyectos Investigación en Salud (MLMC: DTS20/00138); Fundación Atresmedia (to ML and RN), Fundación La Caixa (to ML and RN); la Caixa Foundation Program HR17-00601 (to MLM-C); Gilead Sciences International Research Scholars Program in Liver Disease (to MVR); and the European Foundation for the Study of Diabetes (to RN and GS). This research also received funding from the European Community’s H2020 Framework Programme (ERC Synergy Grant-2019-WATCH-810331, to RN, VP and MS). The Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and the Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd) are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation bioGUNE (SEV-2016- 0644) to CIC.ElsevierUniversidad de Cantabria20232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/30394Molecular Metabolism, 2023, 75, 101776reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/303942026-06-02T12:39:31Z
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