Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
基本信息
- 批准号:9017999
- 负责人:
- 金额:$ 73.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-07 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAcuteAddressAgeAgonistBRD2 geneBeta CellBindingBlood GlucoseBrainBromodomainCREB1 geneCell NucleusCellsComplexConsensusCoupledCyclic AMPCyclic AMP-Dependent Protein KinasesDeacetylaseDeacetylationDefectEP300 geneEmbryoEquilibriumFOXO1A geneFamilyFamily memberFastingFibroblastsFutureGene ExpressionGene TargetingGenesGenetic TranscriptionGlucagonGluconeogenesisGlucoseGrantHepaticHepatocyteHistone DeacetylaseHistonesHormonesHourHyperglycemiaImmune SeraInsulinInsulin ResistanceIslets of LangerhansKineticsKnock-outKnockout MiceLeucine ZippersLiverLong-Term EffectsLoxP-flanked alleleMediatingMethylationMonitorMono-SMusMutant Strains MiceMutationNuclearPCAF genePathway interactionsPhosphorylationPhosphorylation SiteProcessProtein DephosphorylationProtein Kinase InhibitorsProteinsProteomicsRNA InterferenceReceptor SignalingRecruitment ActivityRegulationResistanceRoleSignal TransductionSkeletal MuscleStructure of beta Cell of isletTestingTissuesTransactivationTranscription CoactivatorTransferaseUbiquitinationUp-RegulationWorkattenuationbasecell typecofactorfasting glucosefeedingglucagon-like peptideglucose productionhepatic gluconeogenesishistone methylationimprovedin vivoinhibitor/antagonistinsightinsulin secretionknock-downmembermulticatalytic endopeptidase complexmutantoverexpressionpancreatic islet functionparalogous genepeptide hormoneprogramspromoterprotein kinase inhibitorresponsesalt-inducible kinasetranscription factorubiquitin-protein ligase
项目摘要
Under fasting conditions, increases in circulating glucagon stimulate hepatic glucose production via induction of the cAMP pathway. Conversely, increases in gut-derived glucagon-like peptide 1 (GLP1) during feeding enhance glucose clearance by promoting insulin release. The transcription factor CREB is thought to mediate long term effects of both peptide hormones, following its phosphorylation by PKA and association with CBP/P300. The transcriptional response to cAMP follows burst-attenuation kinetics; CREB activity peaks after 1 hour of stimulation, returning to baseline after 4-6 hours.
In addition to their effects on CREB phosphorylation, glucagon and GLP1 also increase CREB activity by stimulating its association with the cAMP Regulated Transcriptional Coactivators (CRTCs/TORCs), latent cytoplasmic CREB cofactors that translocate to the nucleus following their dephosphorylation in response to cAMP. CRTC1 is expressed only in brain, while CRTC2 and CRTC3 are co-expressed in most tissues. The extent to which CRTC2 and CRTC3 function on overlapping or distinct subsets of CREB target genes is unclear, however. In the previous grant period, we showed that the CREB/CRTC2 pathway contributes importantly to fasting glucose production; acute depletion of CRTC2 in liver substantially lowers blood glucose concentrations and gluconeogenic gene expression, while over-expression of wild-type and to a greater extent phosphorylation-defective CRTC2 increases gluconeogenesis.
By contrast with effects of acute hepatic CRTC2 knockdown, mice with a whole-body knockout of CRTC2 show only modest reductions in fasting glucose levels; and they develop an insulin secretion defect as they age. These results point to the involvement of additional CREB coactivators that compensate for loss of CRTC2 in liver, and they suggest that CRTC2 expression in pancreatic islets also modulates circulating glucose concentrations through its effects on insulin secretion. Supporting the latter, MafA, a beta cell transcription factor that is required for insulin secretion, is strongly upregulated by CREB and CRTC2.
Proposed studies during the upcoming grant period focus on the hypothesis that members of the CRTC family exert overlapping effects on CREB activity. The importance of a newly identified CREB interacting protein in potentiating CREB activity and compensating for loss of CRTC2 in CRTC2 mutant mice will be tested. Finally the role of a potent CREB inhibitor, which is upregulated in pancreatic islets under hyperglycemic conditions, in promoting resistance to Gs-coupled receptor signaling, will be evaluated.
Three aims are proposed; they extend the previous work by addressing the mechanisms by which the CREB pathway promotes gluconeogenesis in liver and facilitates insulin secretion from pancreatic islets.
In Aim 1, we will use mice with floxed alleles of CRTC2 and CRTC3 to evaluate the relative roles of these
coactivators in modulating hepatic gluconeogenesis and insulin secretion. We will generate mice with tissue specific knockouts of CRTC2 and CRTC3 in liver or pancreatic islets. Do CRTC2 and CRTC3 exert overlapping effects on gluconeogenic gene expression in liver? Do they promote insulin secretion by upregulating the leucine zipper factor MafA?
In Aim 2, we will test the role of BRD2-a bromodomain protein identified in a proteomic screen for CREB associated proteins- in stimulating expression of gluconeogenic genes. We will characterize domains in BRD2 and CREB that mediate this interaction; and the role of CREB acetylation in modulating the BRD2:CREB association will also be tested. We will evaluate whether inhibition of BRD2, through administration of a selective bromodomain inhibitor, improves glucose levels in the setting of insulin resistance.
In Aim 3, we will examine the mechanism by which CREB target gene expression in pancreatic islets is down-regulated in insulin resistance. In particular, we will investigate the role of Protein Kinase Inhibitor beta (PKIB) in interfering with GLP1 and other hormones, following its upregulation in response to hyperglycemia: PKIB knockout mice will be used to determine whether depletion of this inhibitor improves pancreatic islet function in the setting of insulin resistance.
Taken together, the proposed studies will provide new insight into mechanisms by which glucagon and GLP1 promote glucose balance through their effects on the CREB pathway in liver and pancreatic beta cells.
在禁食条件下,循环胰高血糖素的增加通过诱导 cAMP 途径刺激肝葡萄糖的产生。相反,进食期间肠源性胰高血糖素样肽 1 (GLP1) 的增加可通过促进胰岛素释放来增强葡萄糖清除率。转录因子 CREB 被 PKA 磷酸化并与 CBP/P300 相关,被认为介导两种肽激素的长期作用。对 cAMP 的转录反应遵循突发衰减动力学; CREB 活性在刺激 1 小时后达到峰值,4-6 小时后恢复到基线。
除了对 CREB 磷酸化的影响外,胰高血糖素和 GLP1 还可以通过刺激 CREB 与 cAMP 调节转录辅激活因子 (CRTC/TORC) 的关联来增加 CREB 活性,CRTC 是潜在的细胞质 CREB 辅因子,在响应 cAMP 去磷酸化后易位到细胞核。 CRTC1仅在脑中表达,而CRTC2和CRTC3在大多数组织中共表达。然而,CRTC2 和 CRTC3 在 CREB 靶基因的重叠或不同子集上发挥作用的程度尚不清楚。在之前的资助期间,我们表明 CREB/CRTC2 途径对空腹血糖产生有重要贡献;肝脏中 CRTC2 的急性耗竭会显着降低血糖浓度和糖异生基因表达,而野生型和磷酸化缺陷型 CRTC2 的过度表达在更大程度上会增加糖异生。
与急性肝脏 CRTC2 敲除的效果相比,全身敲除 CRTC2 的小鼠空腹血糖水平仅出现适度下降;随着年龄的增长,他们会出现胰岛素分泌缺陷。这些结果表明额外的 CREB 共激活剂参与补偿了肝脏中 CRTC2 的损失,并且表明胰岛中 CRTC2 的表达还通过其对胰岛素分泌的影响来调节循环葡萄糖浓度。支持后者的是,MafA(一种胰岛素分泌所需的 β 细胞转录因子)被 CREB 和 CRTC2 强烈上调。
在即将到来的资助期内拟议的研究重点是 CRTC 家族成员对 CREB 活动产生重叠影响的假设。将测试新鉴定的 CREB 相互作用蛋白在增强 CREB 活性和补偿 CRTC2 突变小鼠中 CRTC2 损失方面的重要性。最后,将评估有效的 CREB 抑制剂在促进 Gs 偶联受体信号传导抵抗方面的作用,该抑制剂在高血糖条件下在胰岛中表达上调。
提出了三个目标;他们通过解决 CREB 途径促进肝脏糖异生和促进胰岛分泌胰岛素的机制来扩展之前的工作。
在目标 1 中,我们将使用具有 CRTC2 和 CRTC3 等位基因 floxed 的小鼠来评估这些基因的相对作用
调节肝糖异生和胰岛素分泌的共激活剂。我们将培育出肝或胰岛组织特异性敲除 CRTC2 和 CRTC3 的小鼠。 CRTC2 和 CRTC3 对肝脏糖异生基因表达有重叠作用吗?它们是否通过上调亮氨酸拉链因子 MafA 来促进胰岛素分泌?
在目标 2 中,我们将测试 BRD2(一种在 CREB 相关蛋白的蛋白质组筛选中鉴定出的溴结构域蛋白)在刺激糖异生基因表达中的作用。我们将描述 BRD2 和 CREB 中介导这种相互作用的域;还将测试 CREB 乙酰化在调节 BRD2:CREB 关联中的作用。我们将评估通过施用选择性溴结构域抑制剂抑制 BRD2 是否可以改善胰岛素抵抗情况下的血糖水平。
在目标 3 中,我们将研究胰岛中 CREB 靶基因表达在胰岛素抵抗中下调的机制。特别是,我们将研究蛋白激酶抑制剂 β (PKIB) 在干扰 GLP1 和其他激素中的作用,因为它在高血糖反应中上调:PKIB 敲除小鼠将用于确定这种抑制剂的消耗是否会改善胰岛功能胰岛素抵抗的设置。
总而言之,拟议的研究将为胰高血糖素和 GLP1 通过影响肝脏和胰腺 β 细胞中 CREB 通路来促进葡萄糖平衡的机制提供新的见解。
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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MARC R MONTMINY其他文献
MARC R MONTMINY的其他文献
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{{ truncateString('MARC R MONTMINY', 18)}}的其他基金
Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
- 批准号:
10359198 - 财政年份:2019
- 资助金额:
$ 73.05万 - 项目类别:
Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
- 批准号:
8833274 - 财政年份:2014
- 资助金额:
$ 73.05万 - 项目类别:
Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
- 批准号:
8749897 - 财政年份:2014
- 资助金额:
$ 73.05万 - 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
- 批准号:
8449748 - 财政年份:2011
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$ 73.05万 - 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
- 批准号:
8087954 - 财政年份:2011
- 资助金额:
$ 73.05万 - 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
- 批准号:
8638961 - 财政年份:2011
- 资助金额:
$ 73.05万 - 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
- 批准号:
8258301 - 财政年份:2011
- 资助金额:
$ 73.05万 - 项目类别:
REGULATION OF BETA CELL GENES BY GLUCOSE AND INCRETINS
葡萄糖和肠促胰素对 β 细胞基因的调节
- 批准号:
8171328 - 财政年份:2010
- 资助金额:
$ 73.05万 - 项目类别:
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