Acetyl CoA Carboxylase in the Metabolic Control of Inflammation

综述-乙酰辅酶A羧化酶在炎症代谢控制中的作用 新陈代谢适应是炎症诱导和消退的核心，免疫细胞如 巨噬细胞必须迅速重新连接其细胞代谢，才能成功地发挥效应器功能。信令 通过模式识别受体，如Toll样受体和干扰素受体，导致切换到有氧 糖酵解和葡萄糖需求增加，伴随而来的是氧化磷酸化和 脂质β-氧化。矛盾的是，对病原体的反应也增加了脂质的生物合成，这 导致巨噬细胞积聚过多的脂肪。巨噬细胞的代谢失调会导致 免疫反应受损或过度，在解决感染方面造成毁灭性后果。 患有肥胖症和糖尿病等既往疾病的患者尤其有可能反应不足。 并解决病毒和细菌感染问题。尽管我们对免疫新陈代谢的理解取得了重大进展， 炎性巨噬细胞中新生脂肪生成的作用和代谢失调的病因 不清楚。我们的初步研究意外地将乙酰辅酶A羧基酶(ACC)确定为关键酶 调节巨噬细胞的炎症反应，为研究两者之间的联系提供了机会 免疫细胞中的脂质代谢和炎症反应。ACC是一种直接调节De的中心酶 并通过调节乙酰辅酶A水平间接影响转录能力，从而 组蛋白乙酰化和染色质可及性。ACC抑制剂(Firsocoat)用于临床试验 然而，非酒精性脂肪性肝炎(NASH)，ACC在控制炎症反应中的作用 没有上报。为了检验ACC活性对免疫细胞内源性必不可少的总体假设 诱导和消除急性炎症所需的代谢和转录适应，我们 提出两个具体目标：在具体目标1中，我们将检验ACC活性调节诱导和 使用遗传学和药理学方法解决小鼠的急性炎症反应，包括 新的巨噬细胞特异性ACCDKO小鼠，并通过创造巨噬细胞特异性Acacb和Acacb缺陷小鼠。 特异性目标2将确定ACC-2的保守转录、代谢和功能机制。 依赖于炎症的诱导和消退。成功完成这些研究将确定一部小说 在先天免疫反应中ACC在控制炎症和消解中的作用 ACC1和ACC2亚型在进化上的保守性和个体功能。

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.