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

Maria J. Gonzalez-Rellan; Tamara Parracho; Violeta Heras; Amaia Rodriguez; Marcos F. Fondevila; Eva Novoa; Natalia Lima; Marta Varela-Rey; Ana Senra; Maria D.P. Chantada-Vazquez; Cristina Ameneiro; Ganeko Bernardo; David Fernandez-Ramos; Fernando Lopitz-Otsoa; Jon Bilbao; Diana Guallar; Miguel Fidalgo; Susana Bravo; Carlos Dieguez; Maria L. Martinez-Chantar; Oscar Millet; Jose M. Mato; Markus Schwaninger; Vincent Prevot; Javier Crespo; Gema Frühbeck; Paula Iruzubieta; Ruben Nogueiras

doi:10.1016/j.molmet.2023.101776

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

Maria J. Gonzalez-Rellan^*, Tamara Parracho, Violeta Heras, Amaia Rodriguez, Marcos F. Fondevila, Eva Novoa, Natalia Lima, Marta Varela-Rey, Ana Senra, Maria D.P. Chantada-Vazquez, Cristina Ameneiro, Ganeko Bernardo, David Fernandez-Ramos, Fernando Lopitz-Otsoa, Jon Bilbao, Diana Guallar, Miguel Fidalgo, Susana Bravo, Carlos Dieguez, Maria L. Martinez-ChantarOscar Millet, Jose M. Mato, Markus Schwaninger, Vincent Prevot, Javier Crespo, Gema Frühbeck, Paula Iruzubieta, Ruben Nogueiras^*

^*Corresponding author for this work

Institute of Experimental and Clinical Pharmacology and Toxicology

13 Citations (Scopus)

Abstract

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.

Original language	English
Article number	101776
Journal	Molecular Metabolism
Volume	75
Pages (from-to)	101776
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2023.101776
Publication status	Published - 09.2023

Funding

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: RTI2018–101840-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. 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: RTI2018–101840-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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.molmet.2023.101776

Cite this

Gonzalez-Rellan, M. J., Parracho, T., Heras, V., Rodriguez, A., Fondevila, M. F., Novoa, E., Lima, N., Varela-Rey, M., Senra, A., Chantada-Vazquez, M. D. P., Ameneiro, C., Bernardo, G., Fernandez-Ramos, D., Lopitz-Otsoa, F., Bilbao, J., Guallar, D., Fidalgo, M., Bravo, S., Dieguez, C., ... Nogueiras, R. (2023). Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function. Molecular Metabolism, 75, 101776. Article 101776. https://doi.org/10.1016/j.molmet.2023.101776

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title = "Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function",

abstract = "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.",

author = "Gonzalez-Rellan, \{Maria J.\} and Tamara Parracho and Violeta Heras and Amaia Rodriguez and Fondevila, \{Marcos F.\} and Eva Novoa and Natalia Lima and Marta Varela-Rey and Ana Senra and Chantada-Vazquez, \{Maria D.P.\} and Cristina Ameneiro and Ganeko Bernardo and David Fernandez-Ramos and Fernando Lopitz-Otsoa and Jon Bilbao and Diana Guallar and Miguel Fidalgo and Susana Bravo and Carlos Dieguez and Martinez-Chantar, \{Maria L.\} and Oscar Millet and Mato, \{Jose M.\} and Markus Schwaninger and Vincent Prevot and Javier Crespo and Gema Fr{\"u}hbeck and Paula Iruzubieta and Ruben Nogueiras",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = sep,

doi = "10.1016/j.molmet.2023.101776",

language = "English",

volume = "75",

pages = "101776",

journal = "Molecular Metabolism",

issn = "2212-8778",

}

Gonzalez-Rellan, MJ, Parracho, T, Heras, V, Rodriguez, A, Fondevila, MF, Novoa, E, Lima, N, Varela-Rey, M, Senra, A, Chantada-Vazquez, MDP, Ameneiro, C, Bernardo, G, Fernandez-Ramos, D, Lopitz-Otsoa, F, Bilbao, J, Guallar, D, Fidalgo, M, Bravo, S, Dieguez, C, Martinez-Chantar, ML, Millet, O, Mato, JM, Schwaninger, M, Prevot, V, Crespo, J, Frühbeck, G, Iruzubieta, P & Nogueiras, R 2023, 'Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function', Molecular Metabolism, vol. 75, 101776, pp. 101776. https://doi.org/10.1016/j.molmet.2023.101776

TY - JOUR

T1 - Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function

AU - Gonzalez-Rellan, Maria J.

AU - Parracho, Tamara

AU - Heras, Violeta

AU - Rodriguez, Amaia

AU - Fondevila, Marcos F.

AU - Novoa, Eva

AU - Lima, Natalia

AU - Varela-Rey, Marta

AU - Senra, Ana

AU - Chantada-Vazquez, Maria D.P.

AU - Ameneiro, Cristina

AU - Bernardo, Ganeko

AU - Fernandez-Ramos, David

AU - Lopitz-Otsoa, Fernando

AU - Bilbao, Jon

AU - Guallar, Diana

AU - Fidalgo, Miguel

AU - Bravo, Susana

AU - Dieguez, Carlos

AU - Martinez-Chantar, Maria L.

AU - Millet, Oscar

AU - Mato, Jose M.

AU - Schwaninger, Markus

AU - Prevot, Vincent

AU - Crespo, Javier

AU - Frühbeck, Gema

AU - Iruzubieta, Paula

AU - Nogueiras, Ruben

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85165559795

UR - https://www.mendeley.com/catalogue/7db6f907-823a-31fb-9aac-a2c9a22016f6/

U2 - 10.1016/j.molmet.2023.101776

DO - 10.1016/j.molmet.2023.101776

M3 - Journal articles

C2 - 37453647

AN - SCOPUS:85165559795

SN - 2212-8778

VL - 75

SP - 101776

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101776

ER -

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

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