Leveraging glucose transport and the adaptive fasting response to modulate hepatic metabolism
利用葡萄糖转运和适应性禁食反应来调节肝脏代谢
基本信息
- 批准号:10295349
- 负责人:
- 金额:$ 44.82万
- 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:2021-08-25 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AbateAcuteAttenuatedAutophagocytosisBiochemicalCaloriesCarbohydratesCardiovascular systemCell membraneCessation of lifeDataDeoxyglucoseDevelopmentDiabetes MellitusDietDisaccharidesDiseaseExhibitsExtrahepaticFGF21 geneFastingFatty LiverFatty acid glycerol estersGene DeletionGeneticGlucoseGlucose TransporterGoalsHepaticHepatocyteHomeostasisImaging TechniquesIn VitroIndividualInsulinInsulin ResistanceIntravenousKidneyKineticsKnock-outLeadLigandsLiposomesLiverLiver diseasesLocationLysosomesMass Spectrum AnalysisMeasuresMediatingMetabolicMetabolic DiseasesMetabolic PathwayMetabolic syndromeMetabolismMicroscopicModalityMusMutant Strains MiceNon-Insulin-Dependent Diabetes MellitusOralOvernutritionPathway interactionsPeripheralPharmaceutical PreparationsPharmacologyPhenotypePrediabetes syndromeRadiolabeledRegulationResistanceRetinaRoleSLC2A1 geneSignal TransductionSteatohepatitisSubstrate SpecificityTestingTherapeutic EffectThermogenesisTimeTrehalaseTrehaloseWhole Organismadenylate kinasebasecardiovascular risk factorchronic liver diseasedefined contributiondietaryestablished cell linefasting glucoseglucose transportimprovedin vivoin vivo imagingindexinginhibitor/antagonistknock-downlate endosomeliver metabolismmimeticsmouse modelmutantnon-alcoholic fatty liver diseasenovelnovel strategiespreventreceptorresponsesugartherapeutic target
项目摘要
Non-alcoholic fatty liver disease (NAFLD) is a common and morbid metabolic disease that independently predicts development of type 2 diabetes mellitus and its cardiovascular, renal and retinal complications. More than one billion individuals have NAFLD, making this the most common chronic liver disease worldwide. A barrier to effectively treating and preventing this disease and its complications is the lack of effective NAFLD treatments. Our long-term goal is to understand the underlying glucose metabolic pathways that lead to NAFLD, so that we can precisely modulate these pathways to treat or prevent its progression. We identified the hepatic carbohydrate carrier, GLUT8, as a therapeutic target because: (i.) GLUT8 promotes diet-induced hepatic steatosis and metabolic syndrome and (ii.) the disaccharide and glucose mimetic trehalose inhibits GLUT8 and activates an adaptive fasting response (e.g. AMP kinase and autophagy), to reverse hepatic steatosis. The objective here is to define the interaction between hepatocyte glucose transport, trehalose, and adaptive hepatocyte fasting responses. Our preliminary data suggest that acute hepatocyte-selective GLUT8 knockdown and hepatocyte- specific germline GLUT8 gene deletion (GLUT8 LKO mice) each induce hepatocyte fasting signals and peripheral thermogenesis. We therefore hypothesize that genetic and pharmacological hepatocyte GLUT8 blockade induces thermogenesis and confers resistance to hepatic steatosis. The two Specific Aims are to 1) Identify mechanisms by which GLUT8 regulates hepatic and extrahepatic metabolism, and 2) Define mechanisms mediating trehalose-induced thermogenesis and protection from NAFLD. We will accomplish these aims by leveraging novel experimental mouse models and unique in vivo imaging techniques. Completing these aims informs how to optimally target hepatocyte glucose transport to augment hepatocyte and whole-organism energy homeostasis.
非酒精性脂肪性肝病(NAFLD)是一种常见的病态代谢性疾病,可独立预测2型糖尿病及其心血管、肾脏和视网膜并发症的发生。超过10亿人患有非酒精性脂肪肝,使其成为全球最常见的慢性肝病。有效治疗和预防这种疾病及其并发症的一个障碍是缺乏有效的NAFLD治疗。我们的长期目标是了解导致NAFLD的潜在葡萄糖代谢途径,以便我们能够准确地调节这些途径以治疗或防止其进展。我们确定肝脏碳水化合物载体GLUT8为治疗靶点,因为:(I)GLUT8促进饮食诱导的肝脏脂肪变性和代谢综合征和(Ii)二糖和葡萄糖类似物海藻糖抑制GLUT8并激活适应性空腹反应(例如AMP激酶和自噬),以逆转肝脏脂肪变性。这里的目的是确定肝细胞葡萄糖转运、海藻糖和适应性肝细胞禁食反应之间的相互作用。我们的初步数据表明,急性肝细胞选择性GLUT8基因敲除和肝细胞特异性生殖系GLUT8基因缺失(GLUT8 LKO小鼠)均可诱导肝细胞禁食信号和外周产热。因此,我们假设,基因和药物阻断肝细胞GLUT8诱导产热,并对肝脏脂肪变性具有抵抗力。这两个特定的目的是:1)确定GLUT8调节肝脏和肝外代谢的机制;2)确定介导海藻糖诱导的生热和保护NAFLD的机制。我们将通过利用新的实验小鼠模型和独特的体内成像技术来实现这些目标。完成这些目标,提示如何最佳地靶向肝细胞葡萄糖转运,以增强肝细胞和整个机体的能量动态平衡。
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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Brian Jesse DeBosch其他文献
Brian Jesse DeBosch的其他文献
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{{ truncateString('Brian Jesse DeBosch', 18)}}的其他基金
Leveraging arginase biology against metabolic disease
利用精氨酸酶生物学对抗代谢疾病
- 批准号:
10583279 - 财政年份:2023
- 资助金额:
$ 44.82万 - 项目类别:
Leveraging glucose transport and the adaptive fasting response to modulate hepatic metabolism
利用葡萄糖转运和适应性禁食反应来调节肝脏代谢
- 批准号:
10475158 - 财政年份:2021
- 资助金额:
$ 44.82万 - 项目类别:
Leveraging glucose transport and the adaptive fasting response to modulate hepatic metabolism
利用葡萄糖转运和适应性禁食反应来调节肝脏代谢
- 批准号:
10672277 - 财政年份:2021
- 资助金额:
$ 44.82万 - 项目类别:
Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response
通过模仿适应性肝葡萄糖空腹反应来治疗继发性心肌病
- 批准号:
10170418 - 财政年份:2020
- 资助金额:
$ 44.82万 - 项目类别:
Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response
通过模仿适应性肝葡萄糖空腹反应来治疗继发性心肌病
- 批准号:
10442453 - 财政年份:2020
- 资助金额:
$ 44.82万 - 项目类别:
Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response
通过模仿适应性肝葡萄糖空腹反应来治疗继发性心肌病
- 批准号:
10627917 - 财政年份:2020
- 资助金额:
$ 44.82万 - 项目类别:
Biological Effects and Mechanistic Actions of the Natural Disaccharide and Dietary Supplement, Trehalose.
天然二糖和膳食补充剂海藻糖的生物效应和机理作用。
- 批准号:
9809962 - 财政年份:2019
- 资助金额:
$ 44.82万 - 项目类别:
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