Acetyl CoA Carboxylase in the Metabolic Control of Inflammation

摘要：乙酰辅酶a羧化酶在炎症代谢控制中的作用

SUMMARY - Acetyl CoA Carboxylase in the Metabolic Control of Inflammation Metabolic adaptation is central to both the induction and resolution of inflammation, and immune cells such as macrophages must rapidly rewire their cellular metabolism to successfully carry out effector functions. Signaling through pattern recognition receptors, such as Toll-like and interferon receptors, results in a switch to aerobic glycolysis and increased glucose demand, with concomitant downregulation of oxidative phosphorylation and lipid beta-oxidation. Paradoxically, there is also an increase in lipid biosynthesis in response to pathogens, which results in accumulation of excess lipid in macrophages. Metabolic dysregulation in macrophages results in either compromised or overshooting immune responses, resulting in devastating outcomes in resolution of infections. Patients with preexisting conditions such as obesity and diabetes are particularly at risk to inadequately respond to and resolve viral and bacterial infections. Despite major advances in our understanding of immunometabolism, the role of de novo lipogenesis and the etiology of metabolic dysregulation in inflammatory macrophages remains unclear. Our preliminary studies unexpectedly identify Acetyl CoA Carboxylase (ACC) as a key enzyme regulating the inflammatory response in macrophages, providing an opportunity to investigate the link between lipid metabolism and inflammatory responses in immune cells. ACC is a central enzyme directly regulating de novo lipogenesis as well as indirectly affecting transcriptional capacity by regulating acetyl-CoA levels and thus histone acetylation and chromatin accessibility. ACC inhibitors (Firsocostat) are used in clinical trials against non-alcoholic steatohepatitis (NASH), however, a role for ACC in the control of the inflammatory response has not been reported. To test the overall hypothesis that ACC activity is essential for the immune cell-intrinsic metabolic and transcriptional adaptations required for the induction and resolution of acute inflammation, we propose two specific aims: In Specific Aim 1 we will test the hypothesis that ACC activity regulates induction and resolution of the acute inflammatory response in mice, using genetic and pharmacologic approaches including novel macrophage-specific ACCDKO mice, and by creating macrophage-specific Acacb and Acacb deficient mice. Specific Aim 2 will identify the conserved transcriptional, metabolic, and functional mechanisms underlying ACC- dependent induction and resolution of inflammation. Successful completion of these studies will identify a novel role for ACC in controlling inflammation and resolution during innate immune responses and discover evolutionarily conserved and individual functions of ACC1 and ACC2 isoforms.