The NRF2-FBP1 crossregulatory loop and the control of healthy and diseased liver metabolism
NRF2-FBP1 交叉调节环路以及健康和患病肝脏代谢的控制
基本信息
- 批准号:10503841
- 负责人:
- 金额:$ 70.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AKT inhibitionAblationAldolase BAntioxidantsAutocrine CommunicationBindingBiochemicalBiologicalCancer EtiologyCarbohydratesCellsChildChronicCollagenCollagen FiberDDR1 geneDefectDependenceDesmoplasticDevelopmentDown-RegulationEGF geneEnergy MetabolismEnzymesErythroidExhibitsFastingFatty LiverFiberFructoseGenerationsGenesGenetic TranscriptionGluconeogenesisGlucoseGlycogen Storage DiseaseGrowthHepaticHepatocyteHepatomegalyHomeostasisHumanHypertriglyceridemiaHypoglycemiaIndividualInflammationInsulinIsoenzymesKnockout MiceLiverLiver diseasesMAPK1 geneMAPK3 geneMalignant NeoplasmsMalignant neoplasm of liverMalignant neoplasm of pancreasMediatingMessenger RNAMetabolicMetabolic stressMetabolismMolecularMusNuclearNuclear TranslocationOncogenesOncogenicOncoproteinsOverdosePathologyPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhysiologyPlatelet-Derived Growth FactorPost-Translational Protein ProcessingPredispositionPrimary carcinoma of the liver cellsProtein IsoformsProteinsProteolysisProteomicsProto-Oncogene Proteins c-aktResistanceRoleSerineSignal TransductionStressTechnologyTestingTumor Suppressor ProteinsUbiquitinUbiquitinationUp-Regulationchronic liver injurydefense responsegene inductionglucose metabolismglycogen metabolismhypoxia inducible factor 1inhibitorinnovationlipid biosynthesislipid metabolismliver injuryliver metabolismmetabolic phenotypemouse modelnonalcoholic steatohepatitisnoveloverexpressionreceptorrecruitresponsetranscription factortranscriptomicstreatment responsetumor growthtumor metabolismtumorigenesis
项目摘要
Project Summary/Abstract
Fructose bisphosphate phosphatase (FBP1) is the rate-limiting enzyme in gluconeogenesis (GNG), whereas
nuclear factor erythroid-related factor 2 encoded by the NFE2L2 gene (NRF2) is a transcription factor, previously
identified as the master activator of the antioxidant defense response. NRF2 also activates the transcription of
many metabolic genes, especially in liver. We found that Nrf2Act-HEP mice, in which NRF2 was selectively activated
in hepatocytes, and fasted Fbp1ΔHEP mice, in which FBP1 was conditionally deleted in hepatocytes, exhibit similar
metabolic phenotypes, including hypoglycemia, hepatomegaly, hepatosteatosis and hypertriglyceridemia, which
are also manifested by insulin overdosed individuals and glucose- or carbohydrate-deprived FBP1-deficient
children. Given these similarities, we asked whether NRF2 and FBP1 engage in biochemical crosstalk.
Surprisingly, we found that hepatic activation of NRF2 induces FBP1 degradation, mediated by NRF2 induced
EGF and PDGF expression, which through an autocrine signaling mechanism led to activation of ERK1/2 MAP
kinases that phosphorylated FBP1 at serine 271 and triggered its ubiquitination and proteasomal degradation.
Even more surprising was the finding that FBP1 expression led to inhibition of AKT, thereby relieving inhibitory
phosphorylation of GSK3 isozymes, which phosphorylate a degron embedded within the NRF2 molecule and
thereby induce its ubiquitin-dependent proteolysis. These findings led us to hypothesize that the NRF2-FBP1
crossregulatory loop is a key regulator of liver metabolism and homeostasis, whose aberrant function can
promote liver damage and cancer. We plan to test this hypothesis through three specific aims: 1). Investigate
the hypothesis that FBP1 induces NRF2 degradation in periportal hepatocytes by activating GSK3 or enhancing
its recruitment to NRF2; 2). Determine whether NRF2 activation alters liver zonation and contributes to the
metabolic defects caused by FBP1 ablation; 3). Investigate whether NRF2-induced FBP1 degradation or NRF2
upregulation control the progression from chronic metabolic stress to hepatocellular carcinoma. Pursuing these
aims via new mouse models, cell biological studies and highly innovative Seq-Scope technology, which we had
developed for high-content spatial transcriptomic and proteomic profiling of single liver cells, will answer several
critical questions of general importance: 1). What are the non-enzymatic mechanisms through which FBP1 has
a broad effect on liver metabolism beyond its well-studied involvement in GNG? 2). What is the role of NRF2 in
the metabolic alterations caused by FBP1 deficiency? 3). What is the role of a previously described FBP1-
aldolase B interaction in AKT inhibition and GSK3-induced NRF2 degradation? and 4). What is the role of AKT
activation in the metabolic defects and increased susceptibility to oncogenic transformation exhibited by the
FBP1-deficient liver?
项目总结/文摘
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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Michael Karin其他文献
Michael Karin的其他文献
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{{ truncateString('Michael Karin', 18)}}的其他基金
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
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10516935 - 财政年份:2023
- 资助金额:
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Regulation of PDAC metabolism and immunity by collagen and its cleavage products
胶原及其裂解产物对 PDAC 代谢和免疫的调节
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10708168 - 财政年份:2022
- 资助金额:
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Regulation of PDAC metabolism and immunity by collagen and its cleavage products
胶原及其裂解产物对 PDAC 代谢和免疫的调节
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10517874 - 财政年份:2022
- 资助金额:
$ 70.53万 - 项目类别:
The NRF2-FBP1 crossregulatory loop and the control of healthy and diseased liver metabolism
NRF2-FBP1 交叉调节环路以及健康和患病肝脏代谢的控制
- 批准号:
10670920 - 财政年份:2022
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$ 70.53万 - 项目类别:
The effect of cancer cell produced collagen 1 homotrimers on DDR1 signaling activation by microenvironmental collagen 1 fragments.
癌细胞产生的胶原蛋白 1 同源三聚体对微环境胶原蛋白 1 片段激活 DDR1 信号传导的影响。
- 批准号:
10831212 - 财政年份:2022
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$ 70.53万 - 项目类别:
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂
- 批准号:
10182897 - 财政年份:2020
- 资助金额:
$ 70.53万 - 项目类别:
NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
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- 资助金额:
$ 70.53万 - 项目类别:
Control of Lipogenesis and Hepatic Steatosis by Caspase-2
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- 资助金额:
$ 70.53万 - 项目类别:
Control of Lipogenesis and Hepatic Steatosis by Caspase-2
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- 批准号:
10735256 - 财政年份:2019
- 资助金额:
$ 70.53万 - 项目类别:
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