Lipin-1 transcriptional coregulatory activity promotes macrophage pro-resolving response

Lipin-1 转录共调节活性促进巨噬细胞促解析反应

• 批准号: 10584961
• 负责人: Matthew Dale Woolard
• 金额: $ 56.2万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584961
• 关键词: Anti-Inflammatory Agents; Arterial Fatty Streak; Atherosclerosis; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Ceramides; Cessation of life; Chronic; Data; Event; Failure; Fatty Acids; Genetic Transcription; Growth; Immunosuppression; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Inflammatory Response; Interleukin-4; Knowledge; Laboratories; Lipids; Macrophage; Maps; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Modeling; Movement; Mus; Myelogenous; Necrosis; Nonesterified Fatty Acids; Pathologic; Pathway interactions; Peritonitis; Phagocytosis; Phosphatidate Phosphatase; Process; Proteins; Regulation; Repression; Research; Resolution; Sphingolipids; Stimulus; Techniques; Testing; Therapeutic; Toxic effect; Zymosan; atheroprotective; burden of illness; cell growth regulation; cost; defined contribution; experimental study; fatty acid metabolism; in vivo; innovation; innovative technologies; insight; lipid metabolism; lipine; mouse model; novel; oxidation; programs; response; restoration; therapeutic target; transcription factor

Despite medical advances, atherosclerotic cardiovascular disease (ACVD) is a leading cause of death. ACVD is caused by chronic inflammatory due to both excessive inflammation and failed inflammation resolution. Unlike inhibition of inflammation that reduces ACVD but increases fatal infections, restoration of inflammation resolution may reduce ACVD without increased fatal infections. Macrophages resolve inflammation by secreting anti-in- flammatory mediators and phagocytosing dead cells in a process termed efferocytosis. Efferocytosis increases intracellular free fatty acids (FA) that must be processed either through β-oxidation, incorporation in glycerolipids or ceramides. The movement of FA into these different pathways is called lipid channeling. Increased β-oxidation is associated with macrophage resolution and is considered atheroprotective, while ceramide metabolism pro- motes inflammation and is considered atherogenic. However, there are several critical questions: 1) Is one path- way more critical to inflammation resolution than the other, 2) does the alteration of one lipid pathway alter the other, 3) how lipid channeling is regulated during resolution and plaque regression. Lipin-1 is a phosphatidic acid phosphatase with transcriptional coregulatory activity. My laboratory showed that macrophage-associated lipin- 1 is needed for inflammation resolution and atherosclerotic regression and likely does this through regulation of FA metabolism, independent of its enzymatic activity. Our central hypothesis is that lipin-1 is a dominant lipid channeling regulator in macrophages, promoting inflammation resolution and atherosclerosis regression by en- hancing β-oxidation and repressing ceramide synthesis. We will test our central hypothesis and accomplish the objective of this application by pursuing three specific aims. Aim 1 will explore the hypothesis that lipin-1 regu- lates the activity of metabolic transcription factors to fine-tune FA metabolic pathways to align with macrophage resolution activity. Aim 2 will examine which FA pathways (FA metabolism, β-oxidation, or ceramide metabolism) are critical to macrophage inflammation resolution response and find if the alteration in one pathway impacts the others. Aim 3 will explore the hypothesis that lipin-1 non-enzymatic activity promotes atherosclerotic regression and map the FA metabolic state of the regressing plaque. These proposed experiments will support the innova- tive idea that lipin-1 in macrophages is a dominant regulator of lipid channeling and promotes inflammation resolution by enhancing beta-oxidation while repressing ceramide synthesis. This application's beneficial impact will be the understanding that fatty acid metabolism is regulated to limit lipotoxicity and promote inflammation resolution to identify therapeutic targets to reduce the burden of atherosclerosis and its pathologic sequelae.

尽管医学进步，动脉粥样硬化性心血管疾病（ACVD）是死亡的主要原因。ACVD是 由过度炎症和炎症消退失败引起的慢性炎症引起。不像 抑制炎症，减少ACVD，但增加致命性感染，恢复炎症消退 可能减少ACVD而不增加致命性感染。巨噬细胞通过分泌抗- 炎性介质和在称为细胞吞噬作用的过程中吞噬死细胞。胞饮作用增加 细胞内游离脂肪酸（FA），必须通过β-氧化、掺入甘油酯 或神经酰胺。FA进入这些不同途径的运动称为脂质通道。β-氧化增加 与巨噬细胞消退有关，被认为具有动脉粥样硬化保护作用，而神经酰胺代谢促进 微粒炎症并被认为是致动脉粥样硬化的。然而，有几个关键问题：1）一条路- 对炎症消退比另一种更重要，2）一种脂质途径的改变是否会改变 其他，3）在消退和斑块消退过程中如何调节脂质通道。Lipin-1是磷脂酸 具有转录共调节活性的磷酸酶。我的实验室显示巨噬细胞相关脂蛋白- 1是炎症消退和动脉粥样硬化消退所需的，并且可能通过调节 FA代谢，独立于其酶活性。我们的中心假设是lipin-1是一种主要的脂质 巨噬细胞中的通道调节剂，促进炎症消退和动脉粥样硬化消退， 促进β-氧化和抑制神经酰胺合成。我们将测试我们的中心假设，并实现 本申请通过追求三个具体目标来实现其目的。目的1：探讨lipin-1调节细胞凋亡的机制。 调节代谢转录因子的活性，以微调FA代谢途径， 决议活动。目标2将检查哪些FA途径（FA代谢、β-氧化或神经酰胺代谢） 是巨噬细胞炎症消退反应的关键，并发现一种途径的改变是否会影响巨噬细胞的炎症反应。 他人目的3将探索脂蛋白-1非酶活性促进动脉粥样硬化消退的假设 并绘制退化斑块的FA代谢状态。这些实验将支持创新。 巨噬细胞中的lipin-1是脂质通道的主要调节剂，并促进炎症 通过增强β-氧化同时抑制神经酰胺合成来解决。该应用程序的有益影响 将是脂肪酸代谢被调节以限制脂毒性和促进炎症 确定治疗靶点以减少动脉粥样硬化及其病理后遗症的负担。