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

• 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
• 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' -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

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的最重要的病因，这是一种严重的炎症性疾病 外分泌胰腺导致胰腺功能的丧失和多种合并症，包括糖尿病和 胰腺癌。因此，对酒精性慢性的机制和代谢基础有更好的理解 胰腺炎（ACP）对于确定早期的治疗靶标具有很大的临床意义。 检测/预防疾病。大多数（〜90％）摄入的酒精（乙醇）在肝脏中通过 酒精脱氢酶（ADH）。但是，在慢性酗酒准备过程中抑制肝ADH 脂肪酸乙酯（FAEES，非氧化代谢产物）的形成，在 在慢性酒精滥用期间，胰腺经常损坏。已知这些酯会造成伤害 胰腺腺泡细胞体外和体内。使用喂食3.5％的肝ADH（ADH-）鹿小鼠 乙醇通过lieber-decarli液体饮食，我们发现脂肪胰腺的形成，并增加了几倍的增加 胰腺和内质网（ER）应力和损伤。此外，我们还发现失活 AMP激活的蛋白激酶（AMPK）α的α，该蛋白激酶通过控制脂质合成和 脂肪酸的β-氧化，在新鲜分离的人胰腺腺泡细胞中，体外暴露于乙醇，在 慢性乙醇进食后，ADH-vs.肝脏正常ADH（ADH+）鹿小鼠的胰腺。在一起，这些 初步发现提出了我们的中心假设，即长期摄入乙醇及其非氧化 肝ADH抑制下的代谢停用胰腺AMPKα，导致形成 胰腺中的大量faees，促成ACP发病机理。这个假设将是 通过在喂养乙醇1和3个月的ADH-DEER小鼠中建立进行性胰腺损伤测试（AIM 1）， 并且慢性乙醇供养会使AMPKα失活，促进了FAEES的形成增加，从而导致 ADH-DEER小鼠的进行性胰腺损伤（AIM 2）。体内发现将在主要人类中得到验证 胰腺腺泡细胞。最后，FAEES在乙醇引起的胰腺腺泡细胞损伤中的作用将是 通过使用Adh-deer小鼠和原代人胰腺腺泡细胞建立（AIM 3）。我们期望一个 在我们的鹿小鼠模型中进行性乙醇引起的胰腺损伤，并确定内源性的作用 乙醇诱导的胰腺腺泡细胞损伤中的FAEES。我们的项目具有创新性，因为我们正在使用 肝ad-deer小鼠模型（肝ADH缺乏的自然变体）和新鲜隔离的人 胰腺腺泡细胞以建立ACP的代谢基础和机制。这个项目将受益 由一个强大的研究人员组成的跨学科团队及其在鹿鼠和人类的研究经验 胰腺腺泡细胞培养模型。总体而言，我们的项目应建立ACP代谢基础并确定 ACP的早期检测/治疗干预的分子靶标。