LXRs Link Lipid Metabolism and Inflammation

LXR 与脂质代谢和炎症有关

• 批准号: 9816647
• 负责人: Ira G Schulman
• 金额: $ 38.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-18 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816647
• 关键词: Alzheimer' s Disease; Anti-inflammatory; Atherosclerosis; Binding; Cells; ChIP-seq; Cholesterol; Cholesterol Homeostasis; Chronic Disease; Data; Diabetes Mellitus; Etiology; FRAP1 gene; Fatty Acids; Feedback; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Goals; Immune response; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Knock-out; Ligands; Link; Liver X Receptor; Mediating; Modeling; Nuclear Hormone Receptors; Nucleic Acid Regulatory Sequences; Pathologic; Pathway interactions; Phase; Play; Regulation; Reporting; Resolution; Role; SRE-1 binding protein; STAT1 protein; Signal Pathway; Signal Transduction; TLR4 gene; Testing; Therapeutic; Unsaturated Fatty Acids; Up-Regulation; Virus Diseases; chromatin immunoprecipitation; genome-wide; genome-wide analysis; in vivo evaluation; influenzavirus; lipid metabolism; macrophage; member; mutant; novel; novel strategies; pathogen; response; synergism; transcription factor

Project Summary: Inflammation plays a role in the response to pathogens and in the etiology of chronic diseases including atherosclerosis, diabetes and Alzheimer’s disease. Not surprisingly, strategies to inhibit the inflammatory response and promote resolution of inflammation are being explored for therapeutic benefit. Recent studies have demonstrated that the response of immune cells to pro- and anti-inflammatory signals is associated with changes in lipid metabolism. Activation of toll-like receptor 4 (TLR4) in macrophages leads to a rapid and transient inhibition of fatty acid synthesis that is followed by a later increase in the synthesis of long chain unsaturated fatty acids. Importantly, fatty acid synthesis at later stages of the inflammatory response has been suggested to play a role in resolving inflammation. The signaling pathways that couple lipid metabolism to inflammation, however, are still being defined. The liver X receptors LXR and LXR are members of the nuclear hormone receptor superfamily of ligand activated transcription factors that control genetic networks involved in fatty acid and cholesterol metabolism. We have uncovered a previously unexplored link between LXR activity and inflammatory signaling. Our data indicates that TLR activation leads to up-regulation of LXR expression in a type I interferon- dependent manner at relatively late stages of the inflammatory response. Signal transducer and activator of transcription 1 (STAT1), an interferon stimulated transcription factor, appears to be necessary for the LXR induction. LXRs are subsequently required for the proper shutdown of type I interferon stimulated gene expression. We hypothesize that LXRs interfere with STAT1 transcriptional activity and contribute to a negative feedback loop that plays a role in resolution of the inflammatory response. Concurrently there is an LXR-dependent increase in gene expression associated with the generation of long chain unsaturated fatty acids with reported anti-inflammatory activity. We propose that the effect of LXRs on fatty acid synthesis requires cooperation with sterol regulatory element binding protein 1 (SREBP1), a second transcriptional regulator of fatty acid synthesis. Furthermore we propose that SREBP1 activity can be regulated via interferon-dependent control of the mammalian target of rapamycin (mTOR). Thus type I interferons integrate LXR and mTOR signaling pathways to establish a specific gene expression network that contributes to resolution of the inflammatory response. The goals of the proposed studies are to define the pathway that controls the inflammation-dependent activation of fatty acid synthesis and to determine the LXR-dependent pathway that shuts down type I interferon signaling. We anticipate that these studies will define a novel interface between lipid metabolism and the inflammatory response and may provide new approaches to promote the resolution of inflammation.

项目概要： 炎症在对病原体的反应和慢性疾病的病因学中起作用，包括 动脉粥样硬化、糖尿病和阿尔茨海默病。毫不奇怪，抑制炎症反应的策略 正在探索炎症的反应和促进炎症消退的治疗益处。最近的研究 已经证明免疫细胞对促炎和抗炎信号的反应与 脂质代谢的变化。巨噬细胞中Toll样受体4（TLR 4）的激活导致细胞内Toll样受体的快速和 脂肪酸合成的短暂抑制，随后是长链合成的增加 不饱和脂肪酸重要的是，在炎症反应的后期阶段脂肪酸的合成已经被证明是重要的。 建议在解决炎症方面发挥作用。将脂质代谢与 然而，炎症仍在定义中。 肝X受体LXR β和LXR β是核激素受体超家族的成员， 配体激活的转录因子，其控制涉及脂肪酸和胆固醇的遗传网络 新陈代谢.我们已经发现了LXR活性与炎症之间的一种以前未探索的联系， 发信号。我们的数据表明TLR激活导致I型干扰素中LXR表达上调- 在炎症反应的相对晚期依赖性方式。信号转导和转录激活 转录因子1（STAT 1）是一种干扰素刺激的转录因子，似乎是LXR所必需的。 诱导随后需要LXR来适当关闭I型干扰素刺激的基因， 表情我们假设LXR干扰STAT 1的转录活性，并导致STAT 1的转录活性降低。 负反馈回路，在炎症反应的解决中发挥作用。同时在 是一种LXR依赖性的基因表达增加，与长链不饱和脂肪酸的产生有关。 据报道具有抗炎活性的脂肪酸。我们认为LXR对脂肪酸的影响 合成需要与固醇调节元件结合蛋白1（SREBP 1）合作， 脂肪酸合成的转录调节因子。此外，我们提出SREBP 1活性可以被调节， 通过干扰素依赖性控制哺乳动物雷帕霉素靶蛋白（mTOR）。因此I型干扰素 整合LXR和mTOR信号通路，建立特异性基因表达网络， 炎症反应的消退。拟议研究的目标是确定 控制脂肪酸合成的炎症依赖性激活，并确定LXR依赖性 阻断I型干扰素信号通路。我们预计这些研究将定义一部小说 脂质代谢和炎症反应之间的界面，并可能提供新的方法， 促进炎症消退。