LXRs Link Lipid Metabolism and Inflammation

LXR 与脂质代谢和炎症有关

基本信息

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
项目类别：
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&apos 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

项目摘要

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，包括抑制炎症的策略也就不足为奇了。最近的研究正在探索缓解和促进炎症消退的治疗效果。已经证明免疫细胞对促炎和抗炎信号的反应与巨噬细胞中 Toll 样受体 4 (TLR4) 的激活会导致脂质代谢的变化。暂时抑制脂肪酸合成，随后长链合成增加重要的是，炎症反应后期的脂肪酸合成已被抑制。建议在解决炎症中发挥作用，将脂质代谢耦合到信号通路。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我们发现了 LXR 活性与炎症之间以前未探索过的联系。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。转录 1 (STAT1) 是一种干扰素刺激的转录因子，似乎是 LXR 所必需的随后需要 LXR 来正确关闭 I 型干扰素刺激的基因。我们认为 LXR 会干扰 STAT1 转录活性并有助于负反馈回路同时在解决炎症反应中发挥作用。是与长链不饱和的产生相关的 LXR 依赖性基因表达增加我们提出 LXR 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) 配合此外，我们提出 SREBP1 活性可以被调节。通过对哺乳动物雷帕霉素靶点（mTOR）的干扰素依赖性控制，从而实现 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，有助于拟议研究的目标是确定炎症反应的途径。控制脂肪酸合成的炎症依赖性激活并确定 LXR 依赖性我们预计这些研究将定义一种新颖的关闭 I 型干扰素信号通路。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。