Role of Alcohol Metabolism in Alcoholic Chronic Pancreatitis

酒精代谢在酒精性慢性胰腺炎中的作用

基本信息

批准号：
9897449
负责人：
BHUPENDRA S KAPHALIA
金额：
$ 34.88万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-20 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897449
关键词：
5&apos -AMP-activated protein kinase Acinar Cell Agonist Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcoholic Pancreatitis Animal Model Animals Attenuated Cell Culture Techniques Cessation of life Chronic Clinical Research Cyclic AMP-Dependent Protein Kinases Deer Mouse Diabetes Mellitus Diet Disease Dose Early Diagnosis Esters Ethanol Ethanol Metabolism Etiology Exocrine pancreas Fatty Acids Fibrosis Hepatic Homeostasis Human Impairment In Vitro Incubated Individual Inflammation Inflammatory Injury Lead Lipids Liquid substance Liver Malignant neoplasm of pancreas Metabolic Metabolism Modeling Molecular Target Nature Oral Oxides Pain Pancreas Pancreatic Injury Pancreatitis Pathogenesis Patients Pharmacology Phenotype Play Prevention Protein Isoforms Research Research Personnel Ribonucleotides Role Signal Transduction Testing Therapeutic Intervention Toxic effect Variant alcohol exposure alcohol induced pancreatic injury alcoholic chronic pancreatitis attenuation cell injury chronic alcohol ingestion chronic pancreatitis clinically significant comorbidity cost disorder prevention endoplasmic reticulum stress experience fatty acid oxidation feeding fomepizole in vivo inhibitor/antagonist innovation lipophilicity mouse model novel oxidation problem drinker therapeutic target

项目摘要

Abstract Chronic alcohol abuse is a single most major etiology of chronic pancreatitis, a serious inflammatory disorder of exocrine pancreas leading to loss of pancreatic functions and multiple co-morbidities including diabetes and pancreatic cancer. Therefore, a better understanding of mechanism and metabolic basis of alcoholic chronic pancreatitis (ACP) is of great clinical significance for identifying its therapeutic targets for early detection/prevention of the disease. Majority (~90%) of ingested alcohol (ethanol) is metabolized in the liver via alcohol dehydrogenase (ADH). However, the inhibition of hepatic ADH during chronic alcohol abuse facilitates formation of fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) by several folds in the pancreas frequently damaged during chronic alcohol abuse. These esters are known to cause injury to pancreatic acinar cells in vitro as well as in vivo. Using hepatic ADH-deficient (ADH-) deer mice fed 3.5% ethanol via Lieber-DeCarli liquid diet, we found formation of fatty pancreas and several fold increases for pancreatic FAEEs, and endoplasmic reticulum (ER) stress and injury. Additionally, we also found inactivation of AMP-activated protein kinase (AMPK)α, which regulates lipid homeostasis via controlling lipid synthesis and β-oxidation of fatty acids, in freshly isolated human pancreatic acinar cells exposed to ethanol in vitro, and in the pancreas of ADH- vs. hepatic normal ADH (ADH+) deer mice after chronic ethanol feeding. Together, these preliminary findings led our central hypothesis that chronic ingestion of ethanol and its nonoxidative metabolism under hepatic ADH inhibition deactivates pancreatic AMPKα resulting into formation of a large quantities of FAEEs in the pancreas, contributing to pathogenesis of ACP. This hypothesis will be tested by establishing progressive pancreatic injury in ADH- deer mice fed ethanol for 1 and 3 months (aim 1), and that chronic ethanol feeding inactivates AMPKα, promotes increased formation of FAEEs resulting into progressive pancreatic injury in ADH- deer mice (aim 2). The in vivo findings will be validated in primary human pancreatic acinar cells. Finally, role of FAEEs in ethanol-induced pancreatic acinar cell injury will be established by using ADH- deer mice and primary human pancreatic acinar cells (aim 3). We expect a progressive ethanol-induced pancreatic injury in our deer mouse model, and to identify the role of endogenous FAEEs in ethanol-induced pancreatic acinar cell injury. Our project is innovative because we are using a hepatic ADH- deer mouse model (a natural variant of hepatic ADH deficiency) and freshly isolated human pancreatic acinar cells to establish the metabolic basis and mechanism of ACP. This project will be benefited by a strong interdisciplinary team of investigators and their research experience with deer mouse and human pancreatic acinar cell culture models. Overall, our project should establish metabolic basis of ACP and identify molecular targets for an early detection/therapeutic intervention of ACP.

抽象的慢性酒精滥用是慢性胰腺炎（一种严重的炎症性疾病）的一个最主要的病因胰腺外分泌的损伤导致胰腺功能丧失和多种并发症，包括糖尿病和因此，更好地了解酒精慢性发病机制和代谢基础。胰腺炎（ACP）对于早期确定其治疗靶点具有重要的临床意义。疾病的检测/预防摄入的大部分（~90%）酒精（乙醇）通过肝脏代谢。然而，长期酗酒期间肝脏 ADH 的抑制会促进。脂肪酸乙酯（FAEE，乙醇的非氧化代谢物）的形成数倍长期酗酒时，胰腺经常受损。已知这些酯会导致胰腺损伤。使用喂食 3.5% 的肝 ADH 缺陷 (ADH-) 鹿小鼠进行体外和体内胰腺腺泡细胞。通过 Lieber-DeCarli 流质饮食摄入乙醇，我们发现脂肪胰腺的形成，并且脂肪胰腺的形成增加了几倍此外，我们还发现胰腺 FAEE 以及内质网 (ER) 应激和损伤。 AMP 激活蛋白激酶 (AMPK)α，通过控制脂质合成和调节脂质稳态脂肪酸的β-氧化，在体外暴露于乙醇的新鲜分离的人胰腺腺泡细胞中，以及在长期乙醇喂养后，ADH- 与肝脏正常 ADH (ADH+) 鹿小鼠的胰腺比较。初步研究结果得出我们的中心假设，即长期摄入乙醇及其非氧化性物质肝脏 ADH 抑制下的代谢使胰腺 AMPKα 失活，从而形成胰腺中存在大量 FAEE，有助于 ACP 的发病机制。通过在喂食乙醇 1 个月和 3 个月的 ADH-鹿小鼠中建立进行性胰腺损伤进行测试（目标 1），慢性乙醇喂养会使 AMPKα 失活，促进 FAEE 形成增加，从而导致 ADH-鹿小鼠进行性胰腺损伤（目标 2）体内研究结果将在原代人类中得到验证。最后，FAEE 在乙醇诱导的胰腺腺泡细胞损伤中的作用。通过使用 ADH-鹿小鼠和原代人胰腺腺泡细胞建立（目标 3）。在我们的鹿小鼠模型中进行性乙醇诱导的胰腺损伤，并确定内源性的作用乙醇诱导的胰腺腺泡细胞损伤中的 FAEE 我们的项目具有创新性，因为我们使用的是肝 ADH-鹿小鼠模型（肝 ADH 缺乏症的天然变体）和新鲜分离的人胰腺腺泡细胞建立ACP的代谢基础和机制将受益于此项目。由强大的跨学科研究团队及其对鹿鼠和人类的研究经验组成总的来说，我们的项目应该建立 ACP 的代谢基础并鉴定。 ACP 早期检测/治疗干预的分子靶点。