Acetyl CoA Carboxylase in the Metabolic Control of Inflammation

摘要-乙酰辅酶A羧化酶在炎症的代谢控制 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它们的细胞代谢以成功地执行效应器功能。信令 通过模式识别受体，如Toll样受体和干扰素受体，导致转换为有氧运动 糖酵解和葡萄糖需求增加，伴随氧化磷酸化下调， 脂质β-氧化。巧合的是，响应病原体，脂质生物合成也增加， 导致过量脂质在巨噬细胞中积累。巨噬细胞中的代谢失调导致 免疫反应受损或过度，导致感染解决的破坏性结果。 患有肥胖和糖尿病等既往疾病的患者尤其有可能无法充分应对 解决病毒和细菌感染。尽管我们对免疫代谢的理解取得了重大进展， 在炎症巨噬细胞中，新生脂肪生成和代谢失调的病因学的作用仍然存在， 不清楚我们的初步研究意外地确定乙酰辅酶A羧化酶（ACC）为关键酶 调节巨噬细胞中的炎症反应，为研究 脂质代谢和免疫细胞的炎症反应。ACC是一种直接调节细胞凋亡的中心酶。 以及通过调节乙酰辅酶A水平间接影响转录能力， 组蛋白乙酰化和染色质可及性。ACC抑制剂（Firsocostat）用于临床试验， 然而，在非酒精性脂肪性肝炎（NASH）中，ACC在控制炎症反应中的作用已经被证实。 没有被报道。为了检验ACC活性对免疫细胞内在免疫应答至关重要的总体假设， 急性炎症的诱导和解决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活性调节诱导的假设， 使用遗传学和药理学方法，包括 新的巨噬细胞特异性ACCDKO小鼠，并通过创建巨噬细胞特异性Acacb和Acacb缺陷小鼠。 具体目标2将确定保守的转录，代谢和功能机制的基础ACC- 炎症的依赖性诱导和消退。成功完成这些研究将确定一个新的 ACC在先天免疫反应中控制炎症和消退的作用， ACC 1和ACC 2同种型的进化保守和个体功能。

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.