Homeostatic role of IRE1a-XBP1-PDI1 in hepatic lipid metabolism
IRE1a-XBP1-PDI1 在肝脂质代谢中的稳态作用
基本信息
- 批准号:8888815
- 负责人:
- 金额:$ 58.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnimalsApolipoproteins BAttenuatedBiochemistryCirrhosisConsumptionCytosolDataDevelopmentDiabetes MellitusDiagnosticDietDiseaseDysplasiaEndoplasmic ReticulumEnvironmentEpidemicEtiologyFatty LiverFibrosisFructoseGenesGenetic ModelsGenetic TranscriptionGrantHealthHealth Care CostsHepaticHepatocyteHomeostasisHumanHyperlipidemiaInflammationInositolInsulin ResistanceInterventionKnockout MiceLinkLipidsLipoproteinsLiverLiver diseasesMass Spectrum AnalysisMediatingMessenger RNAMetabolic DiseasesMetabolic stressMitochondriaModalityMolecular ChaperonesMolecular ProfilingMusNutrientNutritionalNutritional StudyObesityPathogenesisPathway interactionsPhysiologyPlasmaPlayPopulationPrimary carcinoma of the liver cellsProductionPrognostic MarkerProtein BiosynthesisProtein Disulfide IsomeraseProteinsProteomicsRNA SplicingReactive Oxygen SpeciesResearchRoleSignal TransductionSiteSmooth Endoplasmic ReticulumStimulusStressTestingTherapeutic InterventionTimeTriglyceridesVery low density lipoproteinalternative treatmentarmbasecardiovascular disorder riskglycosylationimprovedin vivoinsightintrahepaticlipid metabolismlipid transportmRNA Expressionmicrosomal triglyceride transfer proteinnon-alcoholic fatty livernonalcoholic steatohepatitisnovelnovel therapeutic interventionparticlepreventprotein foldingprotein misfoldingpublic health relevanceresponse
项目摘要
DESCRIPTION (provided by applicant): Approximately 20% of the US population suffers from non-alcoholic fatty liver disease (NAFLD) that can progress to hepatosteatosis, fibrosis, cirrhosis
and hepatocellular carcinoma. Hepatic secretion of VLDL plays an essential role in regulating intrahepatic and intravascular lipid homeostasis. The overproduction of hepatic VLDL characterizes the pathogenesis of hyperlipidemia in obesity and diabetes and contributes significantly to an increased risk of cardiovascular disease. Despite the significant impact of abnormalities in VLDL secretion on human health, fundamental cellular mechanisms that drive VLDL assembly are yet to be understood. Hepatic VLDL assembly and secretion is significantly reduced by protein misfolding in the endoplasmic reticulum (ER) and increased by the adaptive unfolded protein response (UPR). The proposed research will elucidate the mechanistic role of the UPR in maintaining triglyceride (TG) levels in the ER lumen for VLDL assembly. We will vigorously test the hypothesis that changes in the ER protein-folding environment of the hepatocyte activate inositol-requiring kinase1 (IRE1) to splice Xbp1 mRNA to generate XBP1s in response to a nutritional stimulus are key in the etiology of NAFLD and abnormal lipid secretion and hyperlipidemia. Our hypothesis is based on three recent fundamental findings regarding assembly of VLDL. First, we have demonstrated that nutritional excess alters lipid homeostasis and activates the UPR in hepatocytes. Aim 1 will uncover the mechanism that links metabolic stress with protein misfolding in the ER. Aims 2 and 3 focus on how XBP1s is essential role to maintain ER lipid homeostasis. We have demonstrated that XBP1s provides two independent functions for assembly of TG-rich VLDL. First, XBP1s activates transcription of protein disulfide isomerase (Pdi1) to maintain microsomal TG transfer protein (MTP) in an active form to promote lipid assembly with apolipoprotein B (ApoB). Aim 2 will study how nutritional stress reduces MTP activity in a PDI1-dependent manner. Aim 3 will identify the second mechanism by which XBP1s is essential to promote TG-rich VLDL assembly in an MTP-independent manner using a combination of mRNA-Seq and mass spectrometry approaches. Finally, and significantly, our data show that PDI1 promotes oxidative folding of ApoB, thus for the first time uncovering a protein folding substrate for PDI1 in vivo. Aim 4 will use hepatocyte-specific Pdi1-null mice to study how PDI1 promotes ApoB100 oxidative folding and alters interactions with the protein-folding environment (i.e., molecular chaperones). Results from the proposed studies will elucidate the mechanisms by which IRE1/XBP1 maintains hepatocyte lipid homeostasis by partitioning TG into the ER lumen for VLDL assembly. The findings will provide fundamental understanding of mechanisms that govern VLDL maturation, which will facilitate the development of novel therapeutic approaches to treat hepatosteatosis and hyperlipidemia.
描述(由申请人提供):约20%的美国人口患有非酒精性脂肪肝(NAFLD),可进展为脂肪肝、纤维化、肝硬化
和肝细胞癌。肝脏分泌VLDL在调节肝内和血管内脂质稳态中起重要作用。肝脏VLDL的过度产生是肥胖和糖尿病高脂血症发病机制的特征,并显著增加心血管疾病的风险。尽管VLDL分泌异常对人类健康有重大影响,但驱动VLDL组装的基本细胞机制仍有待了解。肝极低密度脂蛋白装配和分泌显着减少蛋白质错误折叠在内质网(ER)和增加的适应性未折叠蛋白反应(UPR)。这项研究将阐明UPR在维持内质网腔中甘油三酯(TG)水平以进行VLDL组装中的机制作用。我们将有力地检验这一假设,即肝细胞的ER蛋白折叠环境的变化激活肌醇需要激酶1 β(IRE 1 β)剪接Xbp 1 mRNA以产生XBP 1,以响应营养刺激,这是NAFLD和异常脂质分泌和高脂血症病因学的关键。我们的假设是基于三个最近的基本发现组装的极低密度脂蛋白。首先,我们已经证明,营养过剩改变脂质体内平衡,激活肝细胞中的UPR。目的1将揭示代谢应激与内质网蛋白质错误折叠之间的联系机制。目的2和3关注XBP 1 s如何在维持ER脂质稳态中发挥重要作用。我们已经证明,XBP 1 s提供了两个独立的功能,丰富的TG极低密度脂蛋白的组装。首先,XBP 1激活蛋白质二硫键异构酶(Pdi 1)的转录,以维持微粒体TG转移蛋白(MTP)处于活性形式,从而促进脂质与载脂蛋白B(Apo B)的组装。目的2将研究营养应激如何以PDI 1依赖的方式降低MTP活性。目的3将确定第二种机制,通过这种机制,XBP 1 s对于以MTP独立的方式促进富含TG的VLDL组装是必不可少的,使用mRNA-Seq和质谱方法的组合。最后,值得注意的是,我们的数据表明,PDI 1促进ApoB的氧化折叠,从而首次揭示了PDI 1在体内的蛋白质折叠底物。目的4将使用肝细胞特异性Pdi 1-null小鼠来研究PDI 1如何促进ApoB 100氧化折叠并改变与蛋白质折叠环境的相互作用(即,分子伴侣)。从拟议的研究结果将阐明IRE 1 β/XBP 1维持肝细胞脂质稳态的机制,通过分区TG进入ER腔的VLDL组装。这些发现将提供对VLDL成熟机制的基本理解,这将有助于开发新的治疗方法来治疗脂肪肝和高脂血症。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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RANDAL J. KAUFMAN其他文献
RANDAL J. KAUFMAN的其他文献
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- 批准号:
10632893 - 财政年份:2023
- 资助金额:
$ 58.5万 - 项目类别:
Overcoming FVIII protein misfolding and cell toxicity
克服 FVIII 蛋白错误折叠和细胞毒性
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10560541 - 财政年份:2022
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Overcoming FVIII protein misfolding and cell toxicity
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- 批准号:
10333189 - 财政年份:2022
- 资助金额:
$ 58.5万 - 项目类别:
Mechanism of ER protein misfolding-induced mitochondrial dysfunction
ER蛋白错误折叠导致线粒体功能障碍的机制
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9448713 - 财政年份:2017
- 资助金额:
$ 58.5万 - 项目类别:
Mechanism of ER Protein Misfolding-Induced Mitochondrial Dysfunction
ER蛋白错误折叠引起线粒体功能障碍的机制
- 批准号:
9750668 - 财政年份:2017
- 资助金额:
$ 58.5万 - 项目类别:
ER stress and UPR in non-alcoholic steatohepatitis and hepatocellular carcinoma
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- 批准号:
9914228 - 财政年份:2016
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$ 58.5万 - 项目类别:
ER stress and UPR in non-alcoholic steatohepatitis and hepatocellular carcinoma
非酒精性脂肪性肝炎和肝细胞癌中的 ER 应激和 UPR
- 批准号:
9113989 - 财政年份:2016
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$ 58.5万 - 项目类别:
ER stress and UPR in non-alcoholic steatohepatitis and hepatocellular carcinoma
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9267948 - 财政年份:2016
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eIF2a phosphorylation as a novel druggable target in CRPC
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8805370 - 财政年份:2015
- 资助金额:
$ 58.5万 - 项目类别:
Homeostatic role of IRE1a-XBP1-PDI1 in hepatic lipid metabolism
IRE1a-XBP1-PDI1 在肝脂质代谢中的稳态作用
- 批准号:
9247167 - 财政年份:2015
- 资助金额:
$ 58.5万 - 项目类别:
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