The Role of DENND5B in Dietary Lipid Absorption
The Role of DENND5B in Dietary Lipid Absorption
批准号:
10661074
负责人:
Scott M Gordon
金额:
$51.19万
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
项目状态:
未结题
起止时间:
2022-07-15 至 2027-05-31
关键词:
AGFG1 geneAcuteAddressAffectApolipoproteins BAtherosclerosisAutophagocytosisBiogenesisBioinformaticsBody CompositionBody mass indexCardiometabolic DiseaseCardiovascular DiseasesCell membraneCellsChylomicronsCirculationCo-ImmunoprecipitationsComplexConsciousDataData SetDietDietary FatsDyslipidemiasEnterocytesEquilibriumEsterificationExhibitsFastingFat-Soluble VitaminFatty acid glycerol estersFistulaFoundationsGenesGolgi ApparatusGuanine Nucleotide Exchange FactorsHealthHigh Fat DietHomeostasisHumanIn VitroIngestionInsulin ResistanceIntestinal AbsorptionIntestinal SecretionsIntestinesKnowledgeLinkLipidsLipolysisLipoproteinsLiteratureLymphMaintenanceMass Spectrum AnalysisMeasurementMeasuresMembrane FusionMetabolicMetabolismMethodsMissionMitochondriaModelingMucous MembraneMusNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsObesityOrganismParticle SizePathway interactionsPeripheralPlasmaPlayProcessProteinsPublishingRegulationResistanceRisk FactorsRoleSecretory VesiclesSucroseTissuesTracerTransmembrane TransportTriglyceridesUnited States National Institutes of HealthVariantVery low density lipoproteinWild Type MouseWorkabsorptioncardiometabolismcardiovascular disorder riskcardiovascular risk factorcell typecrosslinkdietaryexome sequencingexperimental studygene networkgene regulatory networkimprovedinsightintestinal epitheliumlipid metabolismmouse modelnovelparticleresponsesingle-cell RNA sequencingtraffickingtranscriptomeuptake
中文摘要
项目总结
英文摘要
Project Summary
Postprandial plasma triacylglyceride levels are independently associated with risk of cardiovascular
disease. The intestine plays a key role in the regulation of dietary triacylglyceride absorption by
packaging and secreting lipids in chylomicron particles. The intracellular steps of chylomicron
biogenesis and transport have been fairly well described, however, there is a significant gap in our
understanding of the mechanism for the final steps of chylomicron secretion by enterocytes, specifically
post-Golgi transport and secretion. We recently identified a protein that plays a critical role in this
pathway, DENND5B. Our newly generated Dennd5b-/- mouse demonstrates an essential role for this
gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. Dennd5b-deficient mice
are resistant to diet-induced: obesity, changes in plasma lipids, and atherosclerosis. In humans, exome
sequencing studies reveal that a common DENND5B variant is correlated with body mass index. These
studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent
influence on body composition and peripheral lipoprotein metabolism. The overall objective of this
proposal is to gain fundamental knowledge about the process of dietary lipid absorption by the intestine
and to examine the impact of this process on systemic metabolic health. This objective aligns well with
the NIH mission to seek fundamental knowledge about living systems and to apply this knowledge to
enhance health. The Specific Aims of this proposal use our novel mouse model and in vitro
experiments to examine the mechanistic role of DENND5B in the intestine and its systemic metabolic
effects. Aim 1 will quantify the impact of Dennd5b on dietary lipid absorption and generate a
comprehensive spatial single-cell RNAsequencing data set for examination of gene networks that
participate in regulation of dietary lipid absorption. Aim 2 will examine the mechanism underlying
Dennd5b action in CM transport. Furthermore, this aim will use mass spectrometry and interactomics
analysis to expand our understanding of this process by identifying other interacting proteins which may
form a complex to facilitate chylomicron secretion by the intestine. Aim 3 will determine the impact of
Dennd5b on enterocyte metabolic function and peripheral lipid metabolism. Successful completion of
this proposal will fill a significant knowledge gap in the process of dietary lipid absorption. This work will
advance the field by providing mechanistic details for a key step in chylomicron secretion that can affect
systemic lipid homeostasis and metabolic health.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.
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批准号:9983143
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项目类别:
-
资助金额:$24.06万
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财政年份:2018
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负责人:Scott M Gordon
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依托单位:
The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.
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批准号:9765384
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项目类别:
-
资助金额:$24.48万
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财政年份:2018
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负责人:Scott M Gordon
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依托单位:
海外基金