02653nas a2200409 4500008004100000022001400041245014400055210006900199260001600268300000800284490000600292520117700298100002801475700003601503700002001539700001801559700003301577700002901610700003801639700003601677700002601713700003401739700003701773700002701810700002901837700001701866700001901883700002601902700002501928700002001953700001901973700002401992700002902016700003002045700003202075856013602107 2023 eng d a2399-364200aMetabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.0 aMetabolic reprogramming by Acly inhibition using SB204990 alters c2023 Mar 08 a2500 v63 a
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.
1 aSola-García, Alejandro1 aCáliz-Molina, María, Ángeles1 aEspadas, Isabel1 aPetr, Michael1 aPanadero-Morón, Concepción1 aGonzález-Morán, Daniel1 aMartín-Vázquez, María, Eugenia1 aNarbona-Pérez, Álvaro, Jesús1 aLópez-Noriega, Livia1 aMartínez-Corrales, Guillermo1 aLópez-Fernández-Sobrino, Raúl1 aCarmona-Marin, Lina, M1 aMartínez-Force, Enrique1 aYanes, Oscar1 aVinaixa, Maria1 aLópez-López, Daniel1 aReyes, José, Carlos1 aDopazo, Joaquin1 aMartín, Franz1 aGauthier, Benoit, R1 aScheibye-Knudsen, Morten1 aCapilla-González, Vivian1 aMartín-Montalvo, Alejandro uhttps://www.clinbioinfosspa.es/content/metabolic-reprogramming-acly-inhibition-using-sb-204990-alters-glucoregulation-and-modulates