Article
Metabolic Reprogramming by Acly Inhibition Using SB-204990 Alters Glucoregulation and Modulates Molecular Mechanisms Associated with Aging
Author/s | Sola García, Alejandro
Cáliz Molina, María Ángeles Espadas, Isabel Petr, Michael Panadero Morón, Concepción González Morán, Daniel Martín Vázquez, María Eugenia Narbona Pérez, Álvaro Jesús López Noriega, Livia Martínez Corrales, Guillermo Martín Montalvo, Alejandro |
Department | Universidad de Sevilla. Departamento de Biología Celular |
Publication Date | 2023 |
Deposit Date | 2024-06-13 |
Published in |
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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 ... 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. |
Funding agencies | Ministerio de Economía y Competitividad (MINECO). España Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía Consejo Superior de Investigaciones Científicas (CSIC) Nordea Foundation. Dinamarca Novo Nordisk Foundation. Dinamarca Lundbeck Foundation. Dinamarca Ministry of Higher Education and Science of Denmark Instituto de Salud Carlos III |
Project ID. | PI15/00134
PI18/01590 CPII19/00023 PID2021-123965OB-100 P20_00480 202220I059 #02-2017-1749 #NNF17OC0027812 #R324-2019-1492 #0238-00003B CP19/00046 |
Citation | Sola García, A., Cáliz Molina, M.Á., Espadas, I., Petr, M., Panadero Morón, C., González Morán, D.,...,Martín Montalvo, A. (2023). Metabolic Reprogramming by Acly Inhibition Using SB-204990 Alters Glucoregulation and Modulates Molecular Mechanisms Associated with Aging. Communications Biology, 6 (1), 250. https://doi.org/10.1038/s42003-023-04625-4. |
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