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; 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 - 炎症的代谢控制中的乙酰基COA羧化酶 代谢适应是炎症的诱导和分辨率和免疫细胞（例如 巨噬细胞必须迅速重新连接其细胞代谢，以成功地执行效应子功能。信号 通过图案识别受体（例如Toll样和干扰素受体），导致转向有氧运动 糖酵解和增加葡萄糖需求，并随之下调氧化磷酸化和 脂质β-氧化。矛盾的是，脂质生物合成也有所增加，以应对病原体，这 导致巨噬细胞中过量脂质的积累。巨噬细胞中的代谢失调导致任何一种 免疫反应损害或过度射击，从而导致感染分辨率的毁灭性结果。 肥胖和糖尿病等先前存在的患者特别有反应不足的风险 进行病毒和细菌感染。尽管我们对免疫代谢的理解取得了重大进展，但 从头脂肪生成和代谢失调的病因在炎症性巨噬细胞中的作用仍然存在 不清楚。我们的初步研究意外地将乙酰基COA羧化酶（ACC）识别为关键酶 调节巨噬细胞中的炎症反应，提供了一个机会来研究 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 通过调节乙酰-COA水平，从而间接影响转录能力，从而间接影响转录能力 组蛋白乙酰化和染色质的可及性。 ACC抑制剂（FIRSOCOSTAT）用于针对的临床试验 但是，非酒精性脂肪性肝炎（NASH），ACC在控制炎症反应中的作用 没有报道。为了检验总体假设，即ACC活性对于免疫细胞中性至关重要 急性炎症诱导和分辨所需的代谢和转录适应性，我们 提出两个具体目标：在特定目标1中，我们将测试ACC活动调节诱导和的假设 使用遗传和药理方法（包括）包括 新型巨噬细胞特异性的ACCDKO小鼠，以及通过创建巨噬细胞特异性的ACACB和ACACB缺乏小鼠。 特定的目标2将确定所基于的保守转录，代谢和功能机制 炎症的依赖诱导和分辨率。这些研究的成功完成将确定一部小说 ACC在先天免疫反应期间控制炎症和解决方案中的作用并发现 ACC1和ACC2同工型的进化保守和个体功能。