Inflammation and hepatic lipid metabolism
炎症与肝脏脂质代谢
基本信息
- 批准号:10453674
- 负责人:
- 金额:$ 52.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ASCL1 geneAcuteAcyl Coenzyme AAdaptor Signaling ProteinAffinityApoptosisApoptoticAttentionBindingBiologicalCASP6 geneCRISPR/Cas technologyCellsCessation of lifeCoenzyme A LigasesComplexDataDiabetes MellitusDietDiseaseEnsureEnzymesEpidemicEquilibriumEsterificationEventExhibitsFamily memberFastingFatty AcidsFatty LiverFatty acid glycerol estersGene ExpressionGenetic TranscriptionHepaticHepatitisHepatocyteHigh Fat DietHomeostasisHumanIn VitroInflammationInflammatoryInsulin ResistanceInvestigationKnock-inKnock-outKnockout MiceLinkLipidsLiverMetabolicMetabolismMitochondriaMolecularMolecular ConformationMusMutation AnalysisNatureObese MiceObesityObesity EpidemicOuter Mitochondrial MembranePathologyPathway interactionsPatientsPhosphorylationPhosphotransferasesPlayProcessProtein FamilyProtein KinaseProtein Serine/Threonine PhosphataseProteinsRegulationRepressionRoleScaffolding ProteinSignal TransductionSiteStarvationTBK1 geneTimeUncertaintyamlexanoxcytokineenergy balancefatty acid oxidationin vivoinhibitorlipid metabolismliver injurymimeticsmutantnon-alcoholicnon-alcoholic fatty liver diseasenovel therapeutic interventionoxidationpreventreconstitutionrecruitrestorationupstream kinase
项目摘要
Abstract
There is little doubt that we are in the midst of a worldwide epidemic of obesity and diabetes. Among the many
complications of obesity is fatty liver, and its associated disease Nonalcoholic Steatotic Hepatitis (NASH).
However, the manner by which lipid storage and oxidation is controlled in liver is only partly understood. We
hypothesize that inflammation plays a role in this process through the protein kinase TBK1. TBK1 associates
with the key enzyme ACSL1, localizing it to mitochondria for fatty acid oxidation during starvation, and to ER
for fatty acid re-esterification during obesity. Moreover, TBK1 represses the activity of AMPK during obesity,
linking fatty liver to liver damage. We will explore the nature of these pathways with three aims: 1) We will
elucidate the temporal and spatial aspects of the induction and activation of the kinase TBK1 in fasting and
obesity; 2) We will deeply explore the molecular mechanism involved in its interaction with ACSL1; and 3) We
will evaluate the molecular mechanisms whereby TBK1 reduces the activity of AMPK, and how this results in
hepatocellular death and liver damage.
摘要
毫无疑问,我们正处于肥胖和糖尿病的全球流行之中。在众多的
肥胖的并发症是脂肪肝及其相关疾病非酒精性脂肪性肝炎(NASH)。
然而,人们对肝脏中脂质储存和氧化的控制方式只有部分了解。我们
假设炎症通过蛋白激酶TBK1在这一过程中发挥作用。TBK1员工
通过关键酶ACSL1,将其定位于线粒体,在饥饿期间进行脂肪酸氧化,并定位到内质网
用于肥胖期间的脂肪酸再酯化。此外,TBK1在肥胖过程中抑制AMPK的活性,
把脂肪肝和肝脏损伤联系起来。我们将以三个目标探索这些途径的性质:1)我们将
阐明在空腹和非饥饿状态下诱导和激活蛋白酪氨酸激酶1的时间和空间方面。
肥胖;2)深入探讨其与ACSL1相互作用的分子机制;3)我们
将评估TBK1降低AMPK活性的分子机制,以及这如何导致
肝细胞死亡和肝损伤。
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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{{ truncateString('ALAN R. SALTIEL', 18)}}的其他基金
Hormonal regulation of LDL receptor trafficking
LDL 受体运输的激素调节
- 批准号:
10491294 - 财政年份:2021
- 资助金额:
$ 52.54万 - 项目类别:
Hormonal regulation of LDL receptor trafficking
LDL 受体运输的激素调节
- 批准号:
10365256 - 财政年份:2021
- 资助金额:
$ 52.54万 - 项目类别:
Adipose tissue plasticity in health and disease
健康和疾病中的脂肪组织可塑性
- 批准号:
10201590 - 财政年份:2020
- 资助金额:
$ 52.54万 - 项目类别:
Adipose tissue plasticity in health and disease
健康和疾病中的脂肪组织可塑性
- 批准号:
10617185 - 财政年份:2020
- 资助金额:
$ 52.54万 - 项目类别:
Adipose tissue plasticity in health and disease
健康和疾病中的脂肪组织可塑性
- 批准号:
10394928 - 财政年份:2020
- 资助金额:
$ 52.54万 - 项目类别:
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