The role of NADPH production in regulating endoplasmic reticulum function and the progression of non-alcoholic steatohepatitis
NADPH产生在调节内质网功能和非酒精性脂肪性肝炎进展中的作用
基本信息
- 批准号:10386489
- 负责人:
- 金额:$ 1.51万
- 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:2022-01-01 至 2022-05-27
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsAttenuatedBudgetsCell physiologyCellsCessation of lifeCholesterolChronicCitric Acid CycleCommunicationConfocal MicroscopyDataDevelopmentDietDiseaseEndoplasmic ReticulumEnvironmentEquilibriumFatty acid glycerol estersFructoseGenetic TranscriptionGlutathioneGlutathione DisulfideGlutathione ReductaseGoalsHealthHepaticHepatocyteHomeostasisIndividualInflammationIsocitrate DehydrogenaseIsoenzymesKnockout MiceLeadLinkLipidsLiverMediatingMetabolicMetabolic DiseasesMetabolismMitochondriaMitochondrial MatrixMolecularMolecular and Cellular BiologyMusNADPNutrientObesityOrganellesOrganismOutcomeOxidation-ReductionOxidesPathway interactionsPhysiologicalPredispositionProcessProductionProteinsResearchRoleSignal TransductionSourceStable Isotope LabelingStressSystemTestingTissuesTrainingTranslationsTricarboxylic AcidsWorkbaseendoplasmic reticulum stressexperienceexperimental studyglutathione peroxidasein vivolipid metabolismliver injurymitochondrial dysfunctionmitochondrial metabolismnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeuticsnutrient deprivationoxidative damageprematureprotein foldingproteostasispyruvate carrierratiometricsensor
项目摘要
Project Summary
Cellular homeostasis is critical not only for the health of individual cells, but for an organism as a whole.
Dysregulation of cellular processes, such as metabolism, contribute to the development of numerous diseases
that have been difficult to fully characterize and treat thus far. Difficulty with treatment arises in part from the
intricacy of cellular metabolism. The mitochondria are the primary metabolic organelles, and they cooperate
with other organelles, including the endoplasmic reticulum (ER). The ER is responsible for lipid packaging and
oxidative protein folding, and is sensitive to perturbations that disrupt these processes. Perturbations to ER
function, better known as ER stress, result in activation of an adaptive pathway that coordinates transcription,
translation, and metabolism to return the cell to homeostasis. However, chronic ER stress often leads to
disease, including metabolic diseases such as non-alcoholic steatohepatitis (NASH). To date, NASH research
has focused on either the mitochondria or ER, but not both. I recently showed that flux through the
mitochondrial tricarboxylic acid (TCA) cycle impacts ER homeostasis through cellular redox signaling via
NADPH and glutathione. This observation led to the hypothesis that TCA flux could communicate nutrient
availability to the ER through NADPH and glutathione in an effort to balance the cellular redox budget and
prime the ER for an influx of proteins or lipids. This also led to the hypothesis that redox communication
between the ER and mitochondria results in ER stress-induced NASH. These two hypotheses are not mutually
exclusive; it is possible that this redox mechanism is responsible for communicating nutrient status to the ER,
but that it has no impact on NASH progression. Testing these hypotheses has the potential to uncover a novel
mechanism for NASH progression.
In this proposal, I will rigorously test the hypothesis that NADPH and glutathione redox lead to ER stress-
induced NASH when nutrients are abundant. I will utilize animals lacking the TCA isozyme, isocitrate
dehydrogenase (Idh2), which generates NADPH in the mitochondrial matrix. I will assess the susceptibility of
these animals to ER stress and a NASH-promoting diet, while also determining how nutrient availability
regulates pathway-specific NADPH production. Additionally, I will test the hypothesis that redox signals are
communicated from the mitochondria to the ER by assessing compartment-specific levels of NADPH and
glutathione under varied nutrient conditions. The broad goal of this proposal is to clarify the role of NADPH and
glutathione in regulating ER function based on nutrient status. Successful completion of this proposal has the
potential to spur research to develop new therapeutics for NASH, and may also be applied to other metabolic
diseases and metabolically active tissues.
项目总结
项目成果
期刊论文数量(0)
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