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Role of the ER acetyl CoA transporter in alcoholic pancreatitis

ER 乙酰 CoA 转运蛋白在酒精性胰腺炎中的作用

基本信息

批准号：
10582543
负责人：
GUY E GROBLEWSKI
金额：
$ 48.33万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582543
关键词：
Abdominal Pain Acetyl Coenzyme A Acetylation Acetylesterase Acinar Cell Acute Alcohol abuse Alcohol consumption Alcoholic Pancreatitis Alcoholic beverage heavy drinker Alcohols Animals Attenuated Automobile Driving Binding Proteins Biochemical Carrier Proteins Cell Death Cell Fractionation Cellular Stress Cholelithiasis Chronic Cytoplasm Data Development Diet Disease Disease Outcome Disease Progression Edema Endoplasmic Reticulum Environmental Risk Factor Enzymes Exhibits Exocrine pancreas Experimental Models Factor X Fibrosis Food Functional disorder Genes Genetic Genetic Transcription Gland Golgi Apparatus Heavy Drinking Hereditary Spastic Paraplegia Heterozygote Human Immunologics Immunoprecipitation Individual Inflammation Inflammatory Knockout Mice Link Liquid substance Longevity LoxP-flanked allele Lysine Mediating Membrane Membrane Proteins Messenger RNA Modeling Molecular Molecular Chaperones Molecular Target Monitor Morphology Mus Mutation Names Neurodegenerative Disorders Onset of illness Oxidative Stress Induction PERK kinase Pain Pancreas Pancreatic Diseases Pancreatitis Pathologic Pathology Pathway interactions Peptide Initiation Factors Phosphorylation Predisposition Process Production Protein Acetylation Proteins Proteomics Quality Control RNA Splicing Recovery Recurrence Regulation Risk Factors Role Severities Side Signal Transduction Smoking Stress System Tamoxifen Testing Tobacco smoking behavior Toxic effect Transcriptional Regulation Translations Up-Regulation Weight Work acute pancreatitis alcohol response biological adaptation to stress chronic alcohol ingestion chronic pancreatitis disorder risk drinking effective therapy endoplasmic reticulum stress environmental stressor experimental study feeding in vivo inhibitor insight misfolded protein mouse model mutant polarized cell prevent problem drinker programs protein degradation protein expression protein folding protein transport response secretory protein sensor stressor transcription factor transcription factor CHOP

项目摘要

ABSTRACT Chronic pancreatitis (CP), a painful, debilitating disorder of the exocrine pancreas, lacks treatments and strategies to prevent disease progression. Alcohol abuse and smoking are common causes of CP but the mechanisms underlying their toxic effects on the pancreas are unclear. Recently, adaptive mechanisms that prevent pancreatitis with stressors such as alcohol were identified in the pancreatic acinar cell. These adaptive mechanisms involve the endoplasmic reticulum (ER) Unfolded Protein Response (UPR) and the UPR transcription factor, X-box binding protein 1 (XBP1s) that upregulates ER chaperones, ER transporters, and quality control machinery to maintain ER function. Our previous work showed that alcohol administration induces oxidative stress but also upregulates XBP1s and a protective UPR that prevents pathology, while smoking inhibits alcohol induced XBP1s formation, and upregulates a pathologic UPR signal mediated by C/EBP homologous protein (CHOP) resulting in ER dysfunction and pancreatitis. This project investigates molecular determinants of pancreatitis associated with alcohol abuse, smoking and perturbed ER protein folding and trafficking. Reversible Nε-lysine acetylation regulates the efficiency of ER protein transit to Golgi and the secretory pathway. Acetylation of properly folded proteins enables ER-to-Golgi exit, while non- acetylated, misfolded proteins divert to protein degradation systems. Thus, disruption of ER protein acetylation perturbs ER function and protein trafficking. The acetyl CoA transporter, AT-1 mediates ER entry of acetyl CoA from cytoplasm to provide substrate for acetylation. In humans, the AT-1-S113R mutant reduces AT-1 transport capacity, and individuals with this mutant exhibit neurodegenerative disorders. We found that XBP1s regulates AT-1 levels in acinar cells. Moreover, AT-1S113r/+ or acinar-specific AT-1 deficient mice develop mild/ moderate CP and chronic ER stress with elevated XBP1s. Strikingly, AP induction in these mice decreases XBP1s levels and markedly exacerbates CP progression. Our results indicate AT-1 and XBP1s are interdependent and important for pancreas adaption in response to alcohol but when overwhelmed by environmental stressors these adaptive systems fail leading to pathology. Our overarching hypothesis is that chronic acinar cell stress and reduced XBP1s protective programs by drinking/smoking attenuate AT-1 expression, disrupting ER acetylation and ER function, and inducing severe CP. Using experimental models of alcoholic + smoking CP, we will pursue 3 aims. Aim 1 will test whether alcohol consumption/smoking converts mild/moderate CP into severe disease in acinar-specific AT-1 KO mice. Aim 2 will evaluate whether enhanced XBP1s expression or CHOP genetic deletion partially mitigates CP severity in AT-1 KO mice. Aim 3 will investigate ER acetylation pathway regulation of ER protein folding and trafficking as well as ER protein degradation. We expect this project to provide insights into the pathways driving CP development, and pinpoint molecular targets for strategies to halt CP progression.

摘要慢性胰腺炎（CP）是一种痛苦的、使人衰弱的胰腺外分泌紊乱，缺乏治疗，预防疾病进展的策略。酒精滥用和吸烟是CP的常见原因，其对胰腺毒性作用的潜在机制尚不清楚。最近，适应机制，在胰腺腺泡细胞中发现了预防胰腺炎的应激源，如酒精。这些自适应其机制涉及内质网（ER）未折叠蛋白反应（UPR）和UPR 转录因子，上调ER伴侣、ER转运蛋白和质量控制机械保持ER功能。我们之前的研究表明，诱导氧化应激，但也上调XBP 1和预防病理的保护性UPR，吸烟抑制酒精诱导的XBP 1 s的形成，并上调病理性UPR信号， C/EBP同源蛋白（CHOP）导致ER功能障碍和胰腺炎。该项目调查胰腺炎的分子决定因素与酗酒、吸烟和ER蛋白紊乱有关折叠和贩卖。可逆Nε-赖氨酸乙酰化调节内质网蛋白转运至高尔基体的效率和分泌途径。正确折叠的蛋白质的乙酰化使得ER能够到达高尔基体，而非ER能够到达高尔基体。乙酰化、错误折叠的蛋白质转移到蛋白质降解系统。因此，ER蛋白乙酰化的破坏干扰ER功能和蛋白质运输。乙酰辅酶A转运蛋白AT-1介导乙酰辅酶A进入内质网来自细胞质的CoA为乙酰化提供底物。在人类中，AT-1-S113 R突变体减少AT-1 运输能力，并且具有该突变体的个体表现出神经退行性疾病。我们发现，调节腺泡细胞中的AT-1水平。此外，AT-1 S113 r/+或腺泡特异性AT-1缺陷小鼠出现轻度/轻度的免疫缺陷。中度CP和慢性ER应激伴XBP 1升高。引人注目的是，这些小鼠的AP诱导减少 XBP 1 s水平并显著加剧CP进展。我们的研究结果表明AT-1和XBP 1是相互依赖，对胰腺适应酒精很重要，但当被酒精淹没时，这些适应系统的环境压力源失败导致病理学。我们的首要假设是慢性腺泡细胞应激和饮酒/吸烟导致的XBP 1保护程序减少， AT-1表达，破坏ER乙酰化和ER功能，并诱导严重的CP。使用酒精+吸烟CP的实验模型，我们将追求3个目标。目标1将测试酒精是否在腺泡特异性AT-1 KO小鼠中，消费/吸烟将轻度/中度CP转化为严重疾病。目的2 将评估增强的XBP 1 s表达或CHOP基因缺失是否部分减轻了CP的严重程度， AT-1 KO小鼠。目的3研究ER乙酰化途径对ER蛋白折叠和转运的调控，以及ER蛋白降解。我们希望这个项目能提供深入了解驱动CP的途径开发，并为阻止CP进展的策略确定分子靶点。