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, lipi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001102 |
| _version_ | 1797754999702290432 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Maria J. Gonzalez-Rellan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T17:41:36Z |
| format | Article |
| id | doaj.art-534b9501b49e4a008f0846e144ff4da3 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-12T17:41:36Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-534b9501b49e4a008f0846e144ff4da32023-08-04T05:47:36ZengElsevierMolecular Metabolism2212-87782023-09-0175101776Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial functionMaria J. Gonzalez-Rellan0Tamara Parracho1Violeta Heras2Amaia Rodriguez3Marcos F. Fondevila4Eva Novoa5Natalia Lima6Marta Varela-Rey7Ana Senra8Maria D.P. Chantada-Vazquez9Cristina Ameneiro10Ganeko Bernardo11David Fernandez-Ramos12Fernando Lopitz-Otsoa13Jon Bilbao14Diana Guallar15Miguel Fidalgo16Susana Bravo17Carlos Dieguez18Maria L. Martinez-Chantar19Oscar Millet20Jose M. Mato21Markus Schwaninger22Vincent Prevot23Javier Crespo24Gema Frühbeck25Paula Iruzubieta26Ruben Nogueiras27Department of Physiology, CIMUS, University of Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Spain; Corresponding author. Department of Physiology, CIMUS, University of Santiago de Compostela, Spain.Department of Physiology, CIMUS, University of Santiago de Compostela, SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, SpainCIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Spain; Metabolic Research Laboratory, Clínica Universidad de Navarra and IdiSNA, Pamplona, SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, SpainGene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, Santiago de Compostela, SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, SpainProteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15705, A Coruña, SpainDepartment of Biochemistry and Molecular Biology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, SpainCIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, 48160, Bizkaia, SpainCIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, 48160, Bizkaia, SpainCIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, 48160, Bizkaia, SpainCIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, 48160, Bizkaia, SpainDepartment of Biochemistry and Molecular Biology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, SpainProteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15705, A Coruña, SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), SpainCIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, 48160, Bizkaia, SpainLiver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd) Technology, SpainLiver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd) Technology, SpainUniversity of Lübeck, Institute for Experimental and Clinical Pharmacology and Toxicology, Lübeck, GermanyUniv. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, European Genomic Institute for Diabetes (EGID), F-59000, Lille, FranceGastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, SpainCIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Spain; Metabolic Research Laboratory, Clínica Universidad de Navarra and IdiSNA, Pamplona, SpainGastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, SpainDepartment of Physiology, CIMUS, University of Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Spain; Galicia Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain; Corresponding author. Department of Physiology, CIMUS, University of Santiago de Compostela, Spain.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.http://www.sciencedirect.com/science/article/pii/S2212877823001102O-GlcNAcylationMitochondrial dysfunctionNAFLD |
| spellingShingle | 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 Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function Molecular Metabolism O-GlcNAcylation Mitochondrial dysfunction NAFLD |
| title | 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_short | 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 |
| topic | O-GlcNAcylation Mitochondrial dysfunction NAFLD |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001102 |
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