Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging
Abstract ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown....
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-04625-4 |
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| author | Alejandro Sola-García María Ángeles Cáliz-Molina Isabel Espadas Michael Petr Concepción Panadero-Morón Daniel González-Morán María Eugenia Martín-Vázquez Álvaro Jesús Narbona-Pérez Livia López-Noriega Guillermo Martínez-Corrales Raúl López-Fernández-Sobrino Alejandro Castillo-Peña Lina M. Carmona-Marin Enrique Martínez-Force Oscar Yanes Maria Vinaixa Daniel López-López José Carlos Reyes Joaquín Dopazo Franz Martín Benoit R. Gauthier Morten Scheibye-Knudsen Vivian Capilla-González Alejandro Martín-Montalvo |
| author_facet | Alejandro Sola-García María Ángeles Cáliz-Molina Isabel Espadas Michael Petr Concepción Panadero-Morón Daniel González-Morán María Eugenia Martín-Vázquez Álvaro Jesús Narbona-Pérez Livia López-Noriega Guillermo Martínez-Corrales Raúl López-Fernández-Sobrino Alejandro Castillo-Peña Lina M. Carmona-Marin Enrique Martínez-Force Oscar Yanes Maria Vinaixa Daniel López-López José Carlos Reyes Joaquín Dopazo Franz Martín Benoit R. Gauthier Morten Scheibye-Knudsen Vivian Capilla-González Alejandro Martín-Montalvo |
| author_sort | Alejandro Sola-García |
| collection | DOAJ |
| description | Abstract ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases. |
| format | Article |
| id | doaj-art-9deabdbc43f647488b325be7381dd75c |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-9deabdbc43f647488b325be7381dd75c2025-08-20T02:13:02ZengNature PortfolioCommunications Biology2399-36422023-03-016111910.1038/s42003-023-04625-4Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with agingAlejandro Sola-García0María Ángeles Cáliz-Molina1Isabel Espadas2Michael Petr3Concepción Panadero-Morón4Daniel González-Morán5María Eugenia Martín-Vázquez6Álvaro Jesús Narbona-Pérez7Livia López-Noriega8Guillermo Martínez-Corrales9Raúl López-Fernández-Sobrino10Alejandro Castillo-Peña11Lina M. Carmona-Marin12Enrique Martínez-Force13Oscar Yanes14Maria Vinaixa15Daniel López-López16José Carlos Reyes17Joaquín Dopazo18Franz Martín19Benoit R. Gauthier20Morten Scheibye-Knudsen21Vivian Capilla-González22Alejandro Martín-Montalvo23Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideCenter for Healthy Aging, Department of Cellular and Molecular Medicine, University of CopenhagenAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideCenter for Healthy Aging, Department of Cellular and Molecular Medicine, University of CopenhagenInstituto de la Grasa (CSIC), Universidad Pablo de OlavideUniversitat Rovira i Virgili, Department of electronic Engineering & IISPVUniversitat Rovira i Virgili, Department of electronic Engineering & IISPVClinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, c/Manuel Siurot s/nAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideClinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, c/Manuel Siurot s/nAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideCenter for Healthy Aging, Department of Cellular and Molecular Medicine, University of CopenhagenAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAndalusian Molecular Biology and Regenerative Medicine Centre-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de OlavideAbstract ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.https://doi.org/10.1038/s42003-023-04625-4 |
| spellingShingle | Alejandro Sola-García María Ángeles Cáliz-Molina Isabel Espadas Michael Petr Concepción Panadero-Morón Daniel González-Morán María Eugenia Martín-Vázquez Álvaro Jesús Narbona-Pérez Livia López-Noriega Guillermo Martínez-Corrales Raúl López-Fernández-Sobrino Alejandro Castillo-Peña Lina M. Carmona-Marin Enrique Martínez-Force Oscar Yanes Maria Vinaixa Daniel López-López José Carlos Reyes Joaquín Dopazo Franz Martín Benoit R. Gauthier Morten Scheibye-Knudsen Vivian Capilla-González Alejandro Martín-Montalvo Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging Communications Biology |
| title | Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging |
| title_full | Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging |
| title_fullStr | Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging |
| title_full_unstemmed | Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging |
| title_short | Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging |
| title_sort | metabolic reprogramming by acly inhibition using sb 204990 alters glucoregulation and modulates molecular mechanisms associated with aging |
| url | https://doi.org/10.1038/s42003-023-04625-4 |
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