Acetyl CoA Carboxylase in the Metabolic Control of Inflammation

乙酰辅酶A羧化酶在炎症代谢控制中的作用

• 批准号: 10660439
• 负责人: NORBERT LEITINGER
• 金额: $ 62.1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660439
• 关键词: ATAC-seq; Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Acute; Affect; Bacterial Infections; Bioenergetics; Cells; Chromatin; Clinical Trials; Diabetes Mellitus; Down-Regulation; Endotoxemia; Enzymes; Escherichia coli; Etiology; Failure; Gene Expression Profiling; Genetic; Genetic Transcription; Glucose; Histone Acetylation; Homeostasis; Host Defense; Ice; Immune; Immune response; Immune system; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interferon Receptor; Link; Lipids; Macrophage; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mus; Myelogenous; Obesity; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Pattern recognition receptor; Phospholipids; Production; Protein Acetylation; Protein Isoforms; Proteomics; Reaction; Recovery; Reporting; Research; Resolution; Risk; Role; Salmonella; Signal Transduction; Signaling Molecule; Site; Testing; Toll-like receptors; Virus Diseases; aerobic glycolysis; chromatin immunoprecipitation; inhibitor; lipid biosynthesis; lipid mediator; lipid metabolism; lipidomics; membrane synthesis; mouse model; nonalcoholic steatohepatitis; novel; oxidation; pathogen; pharmacologic; recruit; response

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.

摘要 - 乙酰辅酶 A 羧化酶在炎症代谢控制中的作用 代谢适应对于炎症的诱导和消退以及免疫细胞（例如 巨噬细胞必须快速重新连接其细胞代谢才能成功执行效应功能。信令 通过模式识别受体，例如 Toll 样受体和干扰素受体，导致转向有氧运动 糖酵解和葡萄糖需求增加，同时下调氧化磷酸化和 脂质β-氧化。矛盾的是，针对病原体的反应，脂质生物合成也有所增加，这 导致巨噬细胞中过量脂质的积累。巨噬细胞的代谢失调会导致 免疫反应受损或过度，导致感染解决过程中出现毁灭性后果。 患有肥胖和糖尿病等既往疾病的患者尤其面临反应不足的风险 并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， 炎症巨噬细胞中从头脂肪生成的作用和代谢失调的病因学仍然存在 不清楚。我们的初步研究出乎意料地确定乙酰辅酶A羧化酶 (ACC) 是一种关键酶 调节巨噬细胞的炎症反应，为研究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是直接调节de的中枢酶 新生脂肪生成以及通过调节乙酰辅酶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（Firsocostat）用于针对 然而，在非酒精性脂肪性肝炎 (NASH) 中，ACC 在控制炎症反应方面的作用已被证实 没有被报道。检验 ACC 活性对于免疫细胞固有的作用至关重要的总体假设 诱导和解决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 使用遗传和药理学方法解决小鼠的急性炎症反应，包括 新型巨噬细胞特异性 ACCDKO 小鼠，以及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 ACC- 背后的保守转录、代谢和功能机制 炎症的依赖性诱导和消退。成功完成这些研究将确定一种新颖的 ACC 在先天免疫反应过程中控制炎症和消退中的作用并发现 ACC1 和 ACC2 亚型在进化上保守且具有各自的功能。