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

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

Automated summary

A multiomic approach reveals that long-term exposure to the Acly inhibitor SB-204990 can modulate molecular mechanisms associated with aging. ATP-citrate lyase has a crucial role in cellular metabolism, integrating the protein, carbohydrate, and lipid metabolism. In vivo studies using untargeted metabolomics, transcriptomics, and proteomics show that SB-204990 regulates energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, and can prevent the development of metabolic abnormalities associated with an unhealthy diet.