Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

• Published in: Communications biology Vol. 6; no. 1; p. 250
• Main Authors: 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, López-Fernández-Sobrino, Raúl, Carmona-Marin, Lina M., Martínez-Force, Enrique, Yanes, Oscar, Vinaixa, Maria, López-López, Daniel, Reyes, José Carlos, Dopazo, Joaquín, Martín, Franz, Gauthier, Benoit R., Scheibye-Knudsen, Morten, Capilla-González, Vivian, Martín-Montalvo, Alejandro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 631/443/319/1642/137/773; 631/443/319/333/1465; 631/443/7; 64/60; 82/58; Acetylation; Aging; Animals; ATP Citrate (pro-S)-Lyase - metabolism; ATP citrate lyase; Biology; Biomedical and Life Sciences; Carbohydrate metabolism; Diet, High-Fat; Energy metabolism; Folic acid; High fat diet; Histones; Insulin; Insulin resistance; Life Sciences; Lipid Metabolism; Metabolic disorders; Metabolism; Metabolomics; Mice; Mitochondria; Molecular modelling; Protein turnover; Proteomics; TOR protein; Transcriptomics
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04625-4

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. A multiomic approach shows that long-term exposure to the Acly inhibitor SB-204990 modulates molecular mechanisms associated with aging.