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...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artigo |
| Data de publicação: | 2023 |
| País: | España |
| Recursos: | Universidad de Navarra |
| Repositório: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | Inglês |
| OAI Identifier: | oai:dadun.unav.edu:10171/68033 |
| Acesso em linha: | https://hdl.handle.net/10171/68033 |
| Nível de acesso: | Acesso aberto |
| Palavra-chave: | NAFLD O-GlcNAcylation Mitochondrial dysfunction |
| _version_ | 1878738576165830656 |
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| author | Gonzalez-Rellan, M.J. (María J.)|||/items/eb5f3b93-72d6-4030-b4f0-feb2293ebe75 |
| author2 | Parracho, T. (Tamara)|||/items/f34ebaee-7f32-4a0a-9a1b-538e674573f7 Heras, V. (Violeta)|||/items/260bed32-8911-4bc9-b41e-67af44db5ef9 Rodriguez, A. (Amaia)|||/items/50976a5f-9842-47f1-8a9c-508e59996427 Fondevila, M.F. (Marcos F.)|||/items/42515fd5-cb1f-44a3-99aa-b643d79de50b Novoa, E. (Eva)|||/items/766fd1b8-02a2-455c-9709-c565201be738 da-Silva-Lima, N. (Natalia)|||/items/9e088f99-dea7-42cf-8026-21c1027c1af8 Varela-Rey, M. (Marta)|||/items/c142211c-bbe7-4b40-a3ad-8d17134ee686 Senra, A. (Ana)|||/items/f48cb1cd-d1eb-46d4-abc6-c985f6e23cc4 Chantada-Vazquez, P. (Pilar)|||/items/15ebaac2-b075-47bb-bc62-f7ad9fa0c222 Ameneiro, C. (Cristina)|||/items/a8899de9-19dd-41f5-ba90-2571cbdd9584 Bernardo, G. (Ganeko)|||/items/5ef92288-af4e-4e5a-b1d0-ce00708cc8bd Fernández-Ramos, D. (David)|||/items/d5e19220-54fe-4552-ad3a-5bb8150cd786 Lopitz-Otsoa, F. (Fernando)|||/items/5e18ab21-ac81-4254-ae11-9dc9d3213e80 Bilbao, J. (Jon)|||/items/d558ad14-d0b1-4ff0-aa00-e36ee854dac5 Guallar, D. (Diana)|||/items/1dc9d5a7-af90-4a94-86a4-9e3e6b3d4058 Fidalgo, M. (Miguel)|||/items/35c79a24-3ecd-498b-bc11-3a43ce977d46 Bravo, S. (Susana B.)|||/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Dieguez, C. (Carlos)|||/items/54b49b82-82ec-4bb6-9d48-c54fb1d572fb Martinez-Chantar, M.L. (María Luz)|||/items/df06120b-2a53-4074-a155-638f899b2ce5 Millet, O. (Oscar)|||/items/d6bbd577-a3c4-4f18-9dc5-1686de0e0489 Mato, J.M. (José María)|||/items/302dc624-b0d3-4703-90cf-1a97690ebc79 Schwaninger, M. (Markus)|||/items/cfedba68-3192-4bac-813e-ca188cac05b6 Prevot, V. (Vincent)|||/items/0dd0ae31-acd4-4768-b1d7-c3ddd654d79f Crespo, J. (Javier)|||/items/e1581aaa-9a29-4ac2-93ed-b1eecf7f67e7 Frühbeck, G. (Gema)|||/items/7f0b1f72-bc91-4ab0-a3fd-21e9a3fb663b Iruzubieta, P. (Paula)|||/items/46ee3e41-35e4-42da-a08c-0f36aa10cc77 Nogueiras, R. (Rubén)|||/items/d6d4c851-6ed5-47d3-9361-c80bbfae88e6 |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_browse | Ameneiro, C. (Cristina)|||/items/a8899de9-19dd-41f5-ba90-2571cbdd9584 Bernardo, G. (Ganeko)|||/items/5ef92288-af4e-4e5a-b1d0-ce00708cc8bd Bilbao, J. (Jon)|||/items/d558ad14-d0b1-4ff0-aa00-e36ee854dac5 Bravo, S. (Susana B.)|||/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Chantada-Vazquez, P. (Pilar)|||/items/15ebaac2-b075-47bb-bc62-f7ad9fa0c222 Crespo, J. (Javier)|||/items/e1581aaa-9a29-4ac2-93ed-b1eecf7f67e7 Dieguez, C. (Carlos)|||/items/54b49b82-82ec-4bb6-9d48-c54fb1d572fb Fernández-Ramos, D. (David)|||/items/d5e19220-54fe-4552-ad3a-5bb8150cd786 Fidalgo, M. (Miguel)|||/items/35c79a24-3ecd-498b-bc11-3a43ce977d46 Fondevila, M.F. (Marcos F.)|||/items/42515fd5-cb1f-44a3-99aa-b643d79de50b Frühbeck, G. (Gema)|||/items/7f0b1f72-bc91-4ab0-a3fd-21e9a3fb663b Gonzalez-Rellan, M.J. (María J.)|||/items/eb5f3b93-72d6-4030-b4f0-feb2293ebe75 Guallar, D. (Diana)|||/items/1dc9d5a7-af90-4a94-86a4-9e3e6b3d4058 Heras, V. (Violeta)|||/items/260bed32-8911-4bc9-b41e-67af44db5ef9 Iruzubieta, P. (Paula)|||/items/46ee3e41-35e4-42da-a08c-0f36aa10cc77 Lopitz-Otsoa, F. (Fernando)|||/items/5e18ab21-ac81-4254-ae11-9dc9d3213e80 Martinez-Chantar, M.L. (María Luz)|||/items/df06120b-2a53-4074-a155-638f899b2ce5 Mato, J.M. (José María)|||/items/302dc624-b0d3-4703-90cf-1a97690ebc79 Millet, O. (Oscar)|||/items/d6bbd577-a3c4-4f18-9dc5-1686de0e0489 Nogueiras, R. (Rubén)|||/items/d6d4c851-6ed5-47d3-9361-c80bbfae88e6 Novoa, E. (Eva)|||/items/766fd1b8-02a2-455c-9709-c565201be738 Parracho, T. (Tamara)|||/items/f34ebaee-7f32-4a0a-9a1b-538e674573f7 Prevot, V. (Vincent)|||/items/0dd0ae31-acd4-4768-b1d7-c3ddd654d79f Rodriguez, A. (Amaia)|||/items/50976a5f-9842-47f1-8a9c-508e59996427 Schwaninger, M. (Markus)|||/items/cfedba68-3192-4bac-813e-ca188cac05b6 Senra, A. (Ana)|||/items/f48cb1cd-d1eb-46d4-abc6-c985f6e23cc4 Varela-Rey, M. (Marta)|||/items/c142211c-bbe7-4b40-a3ad-8d17134ee686 da-Silva-Lima, N. (Natalia)|||/items/9e088f99-dea7-42cf-8026-21c1027c1af8 |
| author_facet | Gonzalez-Rellan, M.J. (María J.)|||/items/eb5f3b93-72d6-4030-b4f0-feb2293ebe75 Parracho, T. (Tamara)|||/items/f34ebaee-7f32-4a0a-9a1b-538e674573f7 Heras, V. (Violeta)|||/items/260bed32-8911-4bc9-b41e-67af44db5ef9 Rodriguez, A. (Amaia)|||/items/50976a5f-9842-47f1-8a9c-508e59996427 Fondevila, M.F. (Marcos F.)|||/items/42515fd5-cb1f-44a3-99aa-b643d79de50b Novoa, E. (Eva)|||/items/766fd1b8-02a2-455c-9709-c565201be738 da-Silva-Lima, N. (Natalia)|||/items/9e088f99-dea7-42cf-8026-21c1027c1af8 Varela-Rey, M. (Marta)|||/items/c142211c-bbe7-4b40-a3ad-8d17134ee686 Senra, A. (Ana)|||/items/f48cb1cd-d1eb-46d4-abc6-c985f6e23cc4 Chantada-Vazquez, P. (Pilar)|||/items/15ebaac2-b075-47bb-bc62-f7ad9fa0c222 Ameneiro, C. (Cristina)|||/items/a8899de9-19dd-41f5-ba90-2571cbdd9584 Bernardo, G. (Ganeko)|||/items/5ef92288-af4e-4e5a-b1d0-ce00708cc8bd Fernández-Ramos, D. (David)|||/items/d5e19220-54fe-4552-ad3a-5bb8150cd786 Lopitz-Otsoa, F. (Fernando)|||/items/5e18ab21-ac81-4254-ae11-9dc9d3213e80 Bilbao, J. (Jon)|||/items/d558ad14-d0b1-4ff0-aa00-e36ee854dac5 Guallar, D. (Diana)|||/items/1dc9d5a7-af90-4a94-86a4-9e3e6b3d4058 Fidalgo, M. (Miguel)|||/items/35c79a24-3ecd-498b-bc11-3a43ce977d46 Bravo, S. (Susana B.)|||/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Dieguez, C. (Carlos)|||/items/54b49b82-82ec-4bb6-9d48-c54fb1d572fb Martinez-Chantar, M.L. (María Luz)|||/items/df06120b-2a53-4074-a155-638f899b2ce5 Millet, O. (Oscar)|||/items/d6bbd577-a3c4-4f18-9dc5-1686de0e0489 Mato, J.M. (José María)|||/items/302dc624-b0d3-4703-90cf-1a97690ebc79 Schwaninger, M. (Markus)|||/items/cfedba68-3192-4bac-813e-ca188cac05b6 Prevot, V. (Vincent)|||/items/0dd0ae31-acd4-4768-b1d7-c3ddd654d79f Crespo, J. (Javier)|||/items/e1581aaa-9a29-4ac2-93ed-b1eecf7f67e7 Frühbeck, G. (Gema)|||/items/7f0b1f72-bc91-4ab0-a3fd-21e9a3fb663b Iruzubieta, P. (Paula)|||/items/46ee3e41-35e4-42da-a08c-0f36aa10cc77 Nogueiras, R. (Rubén)|||/items/d6d4c851-6ed5-47d3-9361-c80bbfae88e6 |
| author_role | author |
| collection | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_b14c8c85d56be4e61b270efe6d8f4246 |
| institution | Universidad de Navarra |
| instname_str | Universidad de Navarra |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:dadun.unav.edu:10171/68033 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| reponame_str | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| spelling | Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function Gonzalez-Rellan, M.J. (María J.)|||/items/eb5f3b93-72d6-4030-b4f0-feb2293ebe75 Parracho, T. (Tamara)|||/items/f34ebaee-7f32-4a0a-9a1b-538e674573f7 Heras, V. (Violeta)|||/items/260bed32-8911-4bc9-b41e-67af44db5ef9 Rodriguez, A. (Amaia)|||/items/50976a5f-9842-47f1-8a9c-508e59996427 Fondevila, M.F. (Marcos F.)|||/items/42515fd5-cb1f-44a3-99aa-b643d79de50b Novoa, E. (Eva)|||/items/766fd1b8-02a2-455c-9709-c565201be738 da-Silva-Lima, N. (Natalia)|||/items/9e088f99-dea7-42cf-8026-21c1027c1af8 Varela-Rey, M. (Marta)|||/items/c142211c-bbe7-4b40-a3ad-8d17134ee686 Senra, A. (Ana)|||/items/f48cb1cd-d1eb-46d4-abc6-c985f6e23cc4 Chantada-Vazquez, P. (Pilar)|||/items/15ebaac2-b075-47bb-bc62-f7ad9fa0c222 Ameneiro, C. (Cristina)|||/items/a8899de9-19dd-41f5-ba90-2571cbdd9584 Bernardo, G. (Ganeko)|||/items/5ef92288-af4e-4e5a-b1d0-ce00708cc8bd Fernández-Ramos, D. (David)|||/items/d5e19220-54fe-4552-ad3a-5bb8150cd786 Lopitz-Otsoa, F. (Fernando)|||/items/5e18ab21-ac81-4254-ae11-9dc9d3213e80 Bilbao, J. (Jon)|||/items/d558ad14-d0b1-4ff0-aa00-e36ee854dac5 Guallar, D. (Diana)|||/items/1dc9d5a7-af90-4a94-86a4-9e3e6b3d4058 Fidalgo, M. (Miguel)|||/items/35c79a24-3ecd-498b-bc11-3a43ce977d46 Bravo, S. (Susana B.)|||/items/e01e519b-f836-4fcb-86d7-31112734e8e2 Dieguez, C. (Carlos)|||/items/54b49b82-82ec-4bb6-9d48-c54fb1d572fb Martinez-Chantar, M.L. (María Luz)|||/items/df06120b-2a53-4074-a155-638f899b2ce5 Millet, O. (Oscar)|||/items/d6bbd577-a3c4-4f18-9dc5-1686de0e0489 Mato, J.M. (José María)|||/items/302dc624-b0d3-4703-90cf-1a97690ebc79 Schwaninger, M. (Markus)|||/items/cfedba68-3192-4bac-813e-ca188cac05b6 Prevot, V. (Vincent)|||/items/0dd0ae31-acd4-4768-b1d7-c3ddd654d79f Crespo, J. (Javier)|||/items/e1581aaa-9a29-4ac2-93ed-b1eecf7f67e7 Frühbeck, G. (Gema)|||/items/7f0b1f72-bc91-4ab0-a3fd-21e9a3fb663b Iruzubieta, P. (Paula)|||/items/46ee3e41-35e4-42da-a08c-0f36aa10cc77 Nogueiras, R. (Rubén)|||/items/d6d4c851-6ed5-47d3-9361-c80bbfae88e6 NAFLD O-GlcNAcylation Mitochondrial dysfunction 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. https://hdl.handle.net/10171/68033 |
| spellingShingle | Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function Gonzalez-Rellan, M.J. (María J.)|||/items/eb5f3b93-72d6-4030-b4f0-feb2293ebe75 NAFLD O-GlcNAcylation Mitochondrial dysfunction |
| 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 | NAFLD O-GlcNAcylation Mitochondrial dysfunction |
| topic_facet | NAFLD O-GlcNAcylation Mitochondrial dysfunction |
| url | https://hdl.handle.net/10171/68033 |