Depalmitoylation regulates hepatic glucose metabolism
去棕榈酰化调节肝脏葡萄糖代谢
基本信息
- 批准号:10387053
- 负责人:
- 金额:$ 3.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcylationAdipose tissueAmericanBacteriaBiotinBiotinylationBlood GlucoseBody CompositionBody measure procedureC-terminalCardiovascular DiseasesCell membraneCell surfaceCellsChronicChronic Kidney FailureCysteineCytosolDataDevelopmentDiabetes MellitusDiagnosisDrug TargetingEnvironmentEnzymesFatty AcidsFatty acid glycerol estersFellowshipFemaleFluorescent ProbesGluconeogenesisGlucoseGlucose TransporterGlycogenGoalsHepG2HepaticHigh Fat DietHumanHyperglycemiaImmunofluorescence ImmunologicIn VitroIncubatedInsulinInsulin ResistanceInvestigationKnock-outKnockout MiceLabelLigaseLinkLipidsLiverLoxP-flanked alleleMass Spectrum AnalysisMediatingMetabolicMetabolic DiseasesMetabolic PathwayMetabolismMethodsModificationMolecular BiologyMolecular Biology TechniquesMolecular and Cellular BiologyMusN-terminalNon-Insulin-Dependent Diabetes MellitusObesityPalmitatesPhysiciansPhysiologyPlant ResinsPlasmaPlasmidsPost-Translational Protein ProcessingPrimary carcinoma of the liver cellsProcessProtein IsoformsProteinsProteomePyruvateRecording of previous eventsRegulatory PathwayResearchResearch PersonnelRiskRoleSaturated Fatty AcidsScientistStreptavidinTestingTrainingUniversitiesVertebratesVesicleWashingtonWorkblood glucose regulationcareerclaycohortexperiencefasting plasma glucosefatty acid metabolismglucose metabolismglucose tolerancein vivoinhibitor/antagonistinsulin sensitivityinsulin signalingintermolecular interactionlipid metabolismmedical schoolsnovelpalmitoylationresponseskills
项目摘要
PROJECT SUMMARY/ABSTRACT
Hundreds of thousands of Americans are diagnosed with type 2 diabetes every year, increasing their risk of
developing cardiovascular disease and chronic kidney disease. While insulin signaling in the liver typically
modulates blood glucose levels by suppressing the synthesis of new glucose and inducing glucose storage,
hepatic insulin resistance can exacerbate hyperglycemia. Insulin resistance is associated with dysregulated
fatty acid metabolism. Fatty acids can directly modify proteins through a reversible process known as
palmitoylation. Depalmitoylating acyl protein thioesterases (APTs), such as APT1 and APT2, can remove these
posttranslational modifications. Although multiple proteins involved in glucose homeostasis have been shown
to be palmitoylated, the role of depalmitoylases in metabolism is still under investigation. Preliminary data
suggest that APT1 liver knockout (APT1LKO) female mice have insulin resistance, while APT2LKO female
mice demonstrate increased fasting plasma glucose levels. However, the redundancy of APT1 and APT2 in
the glucose metabolic pathway is unclear. The objective of this proposal is to elucidate the mechanisms and
consequences of functional redundancy of APT1 and APT2 in the context of glucose homeostasis. The overall
hypothesis is that depalmitoylation by both APT1 and APT2 regulates hepatic glucose metabolism. Aim 1 of
this proposal will determine the substrate redundancy of APT1 and APT2 using in vitro proximity labeling. This
aim will generate APT-biotin ligase fusion constructs to label proteins proximal to APT1 and APT2. Mass
spectrometry of biotinylated proteins will facilitate identification of shared APT-protein interactions. Aim 2 of this
proposal will investigate the functional redundancy of APT1 and APT2 in murine hepatic glucose metabolism.
Chow- and high fat-fed mice with dual deletion of hepatic APT1 and APT2 will be tested for glucose, insulin,
and pyruvate tolerance. Hepatic insulin signaling will also be evaluated in single and double liver-KO mice. The
long-term goal of the proposed research is to implicate reversible lipid modifications in the development of
metabolic disease.
During the fellowship, the applicant will develop important skills for becoming an independent investigator of
metabolism, emphasizing cellular and molecular biology techniques. The sponsor of this work, Dr. Clay
Semenkovich, has vast experience studying the relationship between fatty acid and glucose metabolism, and
the institutional environment provides supportive, collaborative experts in liver physiology and molecular
biology. Washington University School of Medicine has a long history of helping physician-scientists build
successful careers. The proposed training plan will facilitate the applicant’s transition into becoming an
independent physician-scientist, using research to discover novel targets for treating chronic metabolic
diseases.
项目摘要/摘要
每年有数十万美国人被诊断为2型糖尿病,这增加了他们患2型糖尿病的风险。
罹患心血管疾病和慢性肾脏疾病。而肝脏中的胰岛素信号通常
通过抑制新葡萄糖的合成和诱导葡萄糖储存来调节血糖水平,
肝脏胰岛素抵抗会加重高血糖。胰岛素抵抗与调节失调有关
脂肪酸代谢。脂肪酸可以通过一个可逆的过程直接修饰蛋白质,这个过程称为
棕榈酰化。去丝裂原酰化蛋白硫酯酶(APT),如APT1和APT2,可以去除这些
翻译后修饰。尽管已有多种蛋白质参与了葡萄糖的稳态
对于棕榈酰化,脱氨酶在新陈代谢中的作用仍在研究中。初步数据
提示APT1肝基因敲除雌性小鼠存在胰岛素抵抗,而APT2LKO雌性小鼠存在胰岛素抵抗
小鼠表现出空腹血糖水平升高。然而,APT1和APT2的冗余在
葡萄糖代谢途径尚不清楚。这项建议的目的是阐明机制和
APT1和APT2功能冗余对葡萄糖稳态的影响。整体而言
假说是APT1和APT2的脱氨基转移调节肝脏的葡萄糖代谢。目标1
这项建议将使用体外邻近标记来确定APT1和APT2的底物冗余。这
AIM将产生APT-生物素连接酶融合载体来标记APT1和APT2近端的蛋白质。质量
生物素化蛋白质的光谱分析将有助于识别共享的APT-蛋白质相互作用。目标2
提案将研究APT1和APT2在小鼠肝脏葡萄糖代谢中的功能冗余。
肝脏APT1和APT2双重缺失的高脂饲料喂养小鼠将接受葡萄糖、胰岛素和
和丙酮酸耐受性。肝脏胰岛素信号也将在单肝和双肝KO小鼠中进行评估。这个
这项拟议研究的长期目标是将可逆的脂质修饰与糖尿病的发展联系起来。
代谢性疾病。
在奖学金期间,申请者将发展成为一名独立调查员的重要技能
新陈代谢,强调细胞和分子生物学技术。这项工作的发起人克莱博士
Semenkovich在研究脂肪酸和葡萄糖代谢之间的关系方面拥有丰富的经验,
机构环境为肝脏生理学和分子方面的专家提供支持和协作
生物学。华盛顿大学医学院在帮助内科科学家建立
事业成功。拟议的培训计划将有助于申请者过渡到
独立的内科医生兼科学家,利用研究发现治疗慢性代谢的新靶点
疾病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sarah Lilly Speck的其他文献
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{{ truncateString('Sarah Lilly Speck', 18)}}的其他基金
Depalmitoylation regulates hepatic glucose metabolism
去棕榈酰化调节肝脏葡萄糖代谢
- 批准号:
10478914 - 财政年份:2021
- 资助金额:
$ 3.2万 - 项目类别:
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