Regulation of Carbohydrate Metabolism and Lipogenesis
碳水化合物代谢和脂肪生成的调节
基本信息
- 批准号:8441895
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-10-01 至 2016-09-30
- 项目状态:已结题
- 来源:
- 关键词:14-3-3 ProteinsAffinityAnimal ModelBindingBinding ProteinsBinding SitesBiochemicalCarbohydratesCarbonCell Culture TechniquesCell NucleusComplexConsumptionCrystallographyCyclic AMPDataDevelopmentDiabetes MellitusDietDietary CarbohydratesDiseaseEatingElementsEnsureEnzyme GeneEnzymesEpidemicFaminesFastingFatty AcidsFatty acid glycerol estersFoodFood SupplyFractionationGene ExpressionGenesGenetic TranscriptionGlucoseGoalsHepatocyteHormonalImportinsIn VitroIngestionKetone BodiesKetonesKnowledgeLaboratoriesLife StyleLiverLiver ExtractMalignant NeoplasmsMammalian CellMediatingMetabolicModelingMolecularNuclearNuclear ExportNuclear ImportNutrientNutritionalObesityOrganOverweightPharmaceutical PreparationsPhosphorylationPhysiologicalPopulationPrevention strategyProcessProtein BindingProtein BiosynthesisProtein DephosphorylationProtein Phosphatase 2A Regulatory Subunit PR53Protein phosphatasePublic HealthPyruvate KinaseRattusRegulationResponse ElementsRodentRoleSignal TransductionSiteSourceSpecificitySucroseTestingTimeTissuesTriglyceridesWorkX-Ray Crystallographyabstractingblood glucose regulationcarbohydrate metabolismcarbohydrate receptordesigndietary excessfatty acid metabolismfeedingglucose sensorhypertensive heart diseasein vivoinsightlipid biosynthesisnovelobesity treatmentoxidationpressurepromoterprotein complexpublic health relevanceresponsethree dimensional structuretranscription factor
项目摘要
DESCRIPTION (provided by applicant):
Abstract Evolutionary pressure has favored mechanisms that allow the body to efficiently store nutrients as fat when food is abundant as a safeguard against occasional famine. With the dramatic changes in modern lifestyle including consumption of high carbohydrate and high fat foods, these mechanisms may now be contributing to a major epidemic of obesity in the US where the majority of the population is overweight. Glucose is not only a major fuel of all mammalian tissues but also a source of carbon for fat and protein synthesis. The liver is the principal organ responsible for the conversion of excess dietary carbohydrate into triglycerides. Ingestion of a high carbohydrate diet induces transcription of more than 20 genes involved in the conversion of glucose to storage fat. A transcription factor with specificity for carbohydrate responsive elements (ChRE) found in the promoters of multiple genes required for lipogenesis and which displayed appropriate dietary responsive regulation, was first identified in my laboratory following purification from rat liver and termed "carbohydrate response element binding protein, ChREBP". The complete process by which ChREBP is activated in response to excess carbohydrate in order to induce the transcription of lipogenesis enzyme genes and then is turned off is not yet fully understood. We have shown that glucose and cAMP have antagonistic roles in the regulation of ChREBP activities in part through phosphorylation and dephosphorylation of multiple sites on ChREBP. Glucose stimulates dephosphorylation of at least some of these sites by activating a Xu5P-stimulated protein phosphatase, Xu5P-PP2A. More recently we have found that the interaction of ChREBP with 14-3-3 is one of the most important steps in regulation of the nuclear localization of ChREBP. The phosphorylation of ChREBP enhances the binding to 14-3-3 and is essential for export of ChREBP out of the nucleus under fasting conditions. In addition, we found that certain metabolites in fasted liver, but not in fed liver, promote the interaction of ChREBP with 14-3-3, and thereby export of ChREBP out of the nucleus. We have identified the metabolites as ketone bodies. To characterize the metabolites further we propose to (1) determine the biochemical mechanism by which they promote the interaction between ChREBP and 14-3-3, (2) determine their physiological significance in inhibition of ChREBP activities in hepatocytes, and (3) investigate whether the metabolites are signaling compounds for regulation of the subcellular localization of ChREBP in response to nutrients and fasting in vivo. We also will investigate other glucose signaling compounds in high sucrose fed rat liver extracts that may increase importin ¿ binding and/or destabilize 14-3-3 binding to promote the nuclear import of ChREBP. X-ray crystallography will be used to investigate the mechanisms of metabolite regulation of ChREBP binding to 14-3-3 and importin ¿ at an atomic level.
描述(由申请人提供):
摘要 进化的压力支持这样一种机制,即当食物充足时,身体可以有效地将营养物质储存为脂肪,以防止偶尔的饥荒。随着现代生活方式的巨大变化,包括高碳水化合物和高脂肪食物的消费,这些机制现在可能导致美国肥胖症的主要流行,其中大多数人口超重。葡萄糖不仅是所有哺乳动物组织的主要燃料,也是脂肪和蛋白质合成的碳源。肝脏是负责将过量的膳食碳水化合物转化为甘油三酯的主要器官。摄入高碳水化合物饮食诱导20多个基因的转录,这些基因参与葡萄糖向储存脂肪的转化。在脂肪生成所需的多个基因的启动子中发现了一种对碳水化合物反应元件(ChRE)具有特异性的转录因子,该转录因子显示了适当的饮食反应调节,该转录因子首先在我的实验室中从大鼠肝脏中纯化后鉴定,并被称为“碳水化合物反应元件结合蛋白,ChREBP”。ChREBP响应于过量碳水化合物而被激活以诱导脂肪生成酶基因的转录然后被关闭的完整过程尚未完全理解。我们已经表明,葡萄糖和cAMP在ChREBP活性的调节中具有拮抗作用,部分是通过ChREBP上多个位点的磷酸化和去磷酸化。葡萄糖通过激活Xu 5 P刺激的蛋白磷酸酶Xu 5 P-PP 2A来刺激这些位点中的至少一些的去磷酸化。最近,我们发现ChREBP与14-3-3的相互作用是调节ChREBP核定位的最重要步骤之一。ChREBP的磷酸化增强了与14-3-3的结合,并且在禁食条件下对于ChREBP输出到细胞核外是必需的。此外,我们发现禁食肝脏中的某些代谢物促进ChREBP与14-3-3的相互作用,从而将ChREBP输出到细胞核外,但在进食肝脏中没有。我们已将代谢产物鉴定为酮体。为了进一步表征代谢物,我们建议(1)确定它们促进ChREBP和14-3-3之间相互作用的生化机制,(2)确定它们在肝细胞中抑制ChREBP活性的生理意义,以及(3)研究代谢物是否是响应营养和禁食的体内调节ChREBP亚细胞定位的信号化合物。我们还将研究其他葡萄糖信号化合物在高蔗糖喂养大鼠肝提取物,可能会增加importin结合和/或不稳定14-3-3结合,以促进ChREBP的核输入。X射线晶体学将用于研究代谢物调节ChREBP结合14-3-3和importin?在原子水平上的机制。
项目成果
期刊论文数量(0)
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KOSAKU UYEDA其他文献
KOSAKU UYEDA的其他文献
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{{ truncateString('KOSAKU UYEDA', 18)}}的其他基金
Regulation of Carbohydrate Metabolism and Lipogenesis
碳水化合物代谢和脂肪生成的调节
- 批准号:
8762436 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Regulation of Carbohydrate Metabolism and Lipogenesis
碳水化合物代谢和脂肪生成的调节
- 批准号:
8621976 - 财政年份:2012
- 资助金额:
-- - 项目类别:
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