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:
- 金额:$ 38.96万
- 依托单位:
- 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:
- 关键词:Alzheimer&aposs DiseaseAnti-inflammatoryAtherosclerosisBindingCellsChIP-seqCholesterolCholesterol HomeostasisChronic DiseaseDataDiabetes MellitusEtiologyFRAP1 geneFatty AcidsFeedbackGene ExpressionGenerationsGenesGeneticGenetic TranscriptionGoalsImmune responseInflammationInflammatoryInflammatory ResponseInterferon Type IInterferonsKnock-outLigandsLinkLiver X ReceptorMediatingModelingNuclear Hormone ReceptorsNucleic Acid Regulatory SequencesPathologicPathway interactionsPhasePlayRegulationReportingResolutionRoleSRE-1 binding proteinSTAT1 proteinSignal PathwaySignal TransductionTLR4 geneTestingTherapeuticUnsaturated Fatty AcidsUp-RegulationVirus Diseaseschromatin immunoprecipitationgenome-widegenome-wide analysisin vivo evaluationinfluenzaviruslipid metabolismmacrophagemembermutantnovelnovel strategiespathogenresponsesynergismtranscription 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
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ira G Schulman其他文献
Ira G Schulman的其他文献
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{{ truncateString('Ira G Schulman', 18)}}的其他基金
Tissue Specific Control of Cholesterol Metabolism
胆固醇代谢的组织特异性控制
- 批准号:
10452462 - 财政年份:2022
- 资助金额:
$ 38.96万 - 项目类别:
Tissue Specific Control of Cholesterol Metabolism
胆固醇代谢的组织特异性控制
- 批准号:
10653100 - 财政年份:2022
- 资助金额:
$ 38.96万 - 项目类别:
Regulation of Macrophage Reverse Cholesterol Transport by BRCA1
BRCA1 对巨噬细胞反向胆固醇转运的调节
- 批准号:
8440745 - 财政年份:2012
- 资助金额:
$ 38.96万 - 项目类别:
Regulation of Macrophage Reverse Cholesterol Transport by BRCA1
BRCA1 对巨噬细胞反向胆固醇转运的调节
- 批准号:
8278812 - 财政年份:2012
- 资助金额:
$ 38.96万 - 项目类别:
Subtype Specific LXR Activity Limits Atherosclerosis
亚型特异性 LXR 活性限制动脉粥样硬化
- 批准号:
7887172 - 财政年份:2010
- 资助金额:
$ 38.96万 - 项目类别:
Subtype Specific LXR Activity Limits Atherosclerosis
亚型特异性 LXR 活性限制动脉粥样硬化
- 批准号:
8230549 - 财政年份:2010
- 资助金额:
$ 38.96万 - 项目类别:
Subtype Specific LXR Activity Limits Atherosclerosis
亚型特异性 LXR 活性限制动脉粥样硬化
- 批准号:
8045415 - 财政年份:2010
- 资助金额:
$ 38.96万 - 项目类别:
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