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LXRs Link Lipid Metabolism and Inflammation

LXR 与脂质代谢和炎症有关

基本信息

批准号：
9980385
负责人：
Ira G Schulman
金额：
$ 37.74万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980385
关键词：
Alzheimer&apos s Disease Anti-Inflammatory Agents 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.

项目总结：炎症在对病原体的反应和慢性疾病的病因学中发挥作用，包括动脉粥样硬化、糖尿病和阿尔茨海默病。毫不奇怪，抑制炎症性疾病的策略目前正在探索如何应对和促进炎症的消退，以达到治疗的目的。最新研究已经证明免疫细胞对促炎和抗炎信号的反应与脂类代谢的变化。巨噬细胞中Toll样受体4(TLR4)的激活导致快速和脂肪酸合成的一过性抑制，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建议发挥消炎消炎作用。脂类代谢的信号通路然而，炎症的定义仍在进行中。肝X受体LXR和LXR是核激素受体超家族成员。配体激活转录因子，控制与脂肪酸和胆固醇有关的遗传网络新陈代谢。我们发现了LXR活性和炎症之间以前未被研究过的联系发信号。我们的数据表明，TLR激活导致I型干扰素LXR表达上调。在炎症反应的相对较晚阶段以依赖的方式进行。信号换能器和激活器转录1(STAT1)，一种干扰素刺激的转录因子，似乎是LXR所必需的归纳法。随后需要LXRs来正确关闭I型干扰素刺激基因表情。我们假设LXRs干扰STAT1的转录活性，并有助于在消解炎症反应中起作用的负反馈回路。同时在那里是依赖LXR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LXRs对脂肪酸的影响合成需要与固醇调节元件结合蛋白1(SREBP1)合作，第二个脂肪酸合成的转录调节因子。此外，我们认为SREBP1的活性是可以调节的通过依赖干扰素控制哺乳动物的雷帕霉素靶标(MTOR)。因此，I型干扰素整合LXR和mTOR信号通路，建立一个特异的基因表达网络以消解炎症反应。拟议研究的目标是定义控制炎症依赖的脂肪酸合成的激活并确定LXR依赖的关闭I型干扰素信号的途径。我们预计，这些研究将定义一部小说脂代谢和炎症反应之间的接口，并可能提供新的方法促进炎症消退。