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

尽管医学取得了进步，动脉粥样硬化性心血管疾病(ACVD)仍是主要的死亡原因。ACVD是 由于炎症过度和炎症消退失败而引起的慢性炎症。不像 抑制减少ACVD但增加致命性感染的炎症，恢复炎症消退 可能会在不增加致命感染的情况下减少ACVD。巨噬细胞通过分泌抗炎性细胞因子来消炎 炎性介质和吞噬死亡细胞的过程称为泡沫化。细胞吞噬功能增加 细胞内游离脂肪酸(FA)必须通过β氧化、掺入甘油脂来处理 或者神经酰胺。FA进入这些不同途径的过程称为脂质通道。β氧化增加 与巨噬细胞分解有关，并被认为具有动脉粥样硬化保护作用，而神经酰胺代谢促进动脉粥样硬化。 微尘引起炎症，被认为是致动脉粥样硬化的。然而，有几个关键问题：1)是一条途径-- 对炎症消退更为关键的是，2)一种脂类途径的改变是否改变了 其他，3)脂质通道如何在分解和斑块消退过程中被调节。脂蛋白-1是一种磷脂酸 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的脂类- 1是炎症消退和动脉粥样硬化消退所必需的，可能是通过调节 FA代谢，与其酶活性无关。我们的中心假设是脂类-1是主要的脂类 巨噬细胞通道调节因子促进炎症消退和动脉粥样硬化消退 增强β氧化，抑制神经酰胺合成。我们将测试我们的中心假设，并完成 通过追求三个具体目标来实现这一申请的目标。目标1将探索这样的假设，即脂蛋白-1调节- 延缓代谢转录因子的活性以微调FA代谢途径以与巨噬细胞对齐 解决活动。目标2将检查哪些FA途径(FA代谢、β氧化或神经酰胺代谢) 对巨噬细胞炎症分解反应至关重要，并发现一条途径的改变是否会影响 其他。目的3将探讨脂蛋白-1非酶活性促进动脉粥样硬化消退的假说 并绘制退化斑块的FA代谢状态图。这些拟议的实验将支持创新-- 一种观点认为巨噬细胞中的脂类-1是脂类通道的主要调节因子，并促进炎症 在抑制神经酰胺合成的同时，通过增强β-氧化来分解。此应用程序的有益影响 将理解脂肪酸代谢被调节以限制脂肪毒性和促进炎症 决议确定治疗靶点，以减轻动脉粥样硬化及其病理后遗症的负担。

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.