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发挥着重要作用，包括 动脉粥样硬化、糖尿病和阿尔茨海默病。毫不奇怪，抑制炎症的策略 正在探索反应和促进炎症消退以获得治疗益处。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 (TLR4) 的激活导致快速且 暂时抑制脂肪酸合成，随后长链合成增加 不饱和脂肪酸。重要的是，炎症反应后期的脂肪酸合成已被证实 建议发挥消炎作用。脂质代谢耦合的信号通路 然而，炎症仍在定义中。 肝脏 X 受体 LXR 和 LXR 是核激素受体超家族的成员 配体激活的转录因子控制涉及脂肪酸和胆固醇的遗传网络 代谢。我们发现了 LXR 活性与炎症之间以前未探索过的联系 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 炎症反应相对较晚阶段的依赖方式。信号转换器和激活器 转录 1 (STAT1) 是一种干扰素刺激的转录因子，似乎是 LXR 所必需的 就职。随后需要 LXR 来正确关闭 I 型干扰素刺激的基因 表达。我们假设 LXR 干扰 STAT1 转录活性并有助于 负反馈循环在解决炎症反应中发挥作用。同时有 是与长链不饱和的产生相关的 LXR 依赖性基因表达增加 据报道具有抗炎活性的脂肪酸。我们认为 LXRs 对脂肪酸的影响 合成需要与第二个甾醇调节元件结合蛋白 1 (SREBP1) 配合 脂肪酸合成的转录调节因子。此外，我们建议可以调节 SREBP1 活性 通过对哺乳动物雷帕霉素靶点（mTOR）的干扰素依赖性控制。因此I型干扰素 整合 LXR 和 mTOR 信号通路，建立特定的基因表达网络，有助于 以解决炎症反应。拟议研究的目标是确定途径 控制脂肪酸合成的炎症依赖性激活并确定 LXR 依赖性 关闭 I 型干扰素信号传导的途径。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，可能提供新的方法 促进炎症的消退。