Fatty Acid Ethyl Esters in Ethanol-induced Pancreatitis

脂肪酸乙酯在乙醇诱发的胰腺炎中的作用

• 批准号: 6619844
• 负责人: BHUPENDRA S KAPHALIA
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619844
• 关键词: acyltransferase; alcohol dehydrogenase; alcoholism /alcohol abuse; apoptosis; dosage; enzyme activity; enzyme induction /repression; enzyme inhibitors; esters; ethanol; fatty acids; laboratory mouse; pancreatitis; tissue /cell culture

DESCRIPTION (provided by applicant): Pancreatitis is a major health problem in alcoholics that causes high mortality and morbidity, and after biliary duct diseases, chronic alcohol abuse is the second major cause of chronic pancreatitis. However, the mechanism of alcohol-induced pancreatitis is poorly understood. Oxidative metabolism of ethanol catalyzed by alcohol dehydrogenase (ADH) is negligible in the pancreas, while nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs), catalyzed by FAEE synthase, appears to be the major mechanism of ethanol disposition in the pancreas during chronic alcohol abuse. Surprisingly, very little is known regarding the role of endogenously formed FAEEs in ethanol-induced pancreatitis. Based upon our preliminary studies showing - 14-fold increase in FAEE levels in the pancreas of hepatic ADH-deficient (ADH-) deer mice as compared to those in ADH-normal deer mice, and a dose- and time-dependent formation of FAEEs and FAEE-induced apoptosis upon ethanol exposure of ADH-deficient human hepatocellular carcinoma (HepG2) cells in culture, we hypothesize that increased formation of FAEEs is a triggering event in ethanol-induced pancreatitis, and that FAEEs and FAEE synthase can be early markers of pancreatic injury. Our preliminary studies also indicate that FAEEs are formed in rat pancreatic tumor (AR42J) cells in culture. Therefore, to investigate the toxic potential of endogenously formed FAEEs and elucidate their role in ethanol-induced pancreatic injury, we will use ADH- deer mice and AR42J cells. In Aim 1, we will determine the levels of FAEEs in the plasma and pancreas of ADH- deer mice after ethanol exposure in a dose- and time-dependent manner, and evaluate the biochemical and morphological parameters associated with pancreatic injury. We will evaluate apoptosis in the pancreas of ADH- deer mice, and in AR42J cells, after ethanol exposure (Aim 2). Inhibitors or inducers of FAEE synthase to attenuate or augment formation of FAEEs in AR42J cells, respectively, will be used to further examine the role of endogenously formed FAEEs in ethanol-induced apoptosis and toxicity (Aim 3). Achieving our Specific Aims 1-3 should establish the role of FAEEs in ethanol-induced pancreatic injury, lay the foundation for future human studies to develop these parameters as early markers for ethanol-induced pancreatic damage, and ultimately benefit us in developing new preventive/therapeutic strategies for early intervention before irreversible damage to pancreas occurs.

描述（由申请人提供）：胰腺炎是酗酒者的主要健康问题，导致高死亡率和发病率，仅次于胆管疾病，慢性酒精滥用是慢性胰腺炎的第二大原因。然而，酒精诱导胰腺炎的机制知之甚少。乙醇脱氢酶（ADH）催化的乙醇氧化代谢在胰腺中可以忽略不计，而脂肪酸乙酯（FAEE）合成酶催化的乙醇非氧化代谢脂肪酸乙酯（FAEE），似乎是慢性酒精滥用期间胰腺中乙醇处置的主要机制。令人惊讶的是，很少有人知道的作用，内源性形成FAEE在乙醇诱导的胰腺炎。基于我们的初步研究显示，与ADH正常的鹿小鼠相比，肝脏ADH缺陷型（ADH-）鹿小鼠的胰腺中FAEE水平增加14倍，并且培养物中ADH缺陷型人肝细胞癌（HepG 2）细胞在乙醇暴露后形成剂量和时间依赖性的FAEE和FAEE诱导的细胞凋亡，我们假设FAEE形成的增加是乙醇诱导的胰腺炎的触发事件，FAEE和FAEE合酶可以是胰腺损伤的早期标志物。我们的初步研究还表明，FAEEs在培养的大鼠胰腺肿瘤（AR 42 J）细胞中形成。因此，为了研究内源性形成的FAEE的毒性潜力并阐明其在乙醇诱导的胰腺损伤中的作用，我们将使用ADH-鹿小鼠和AR 42 J细胞。在目的1中，我们将确定乙醇暴露后，以剂量和时间依赖性的方式在ADH-鹿小鼠的血浆和胰腺中FAEEs的水平，并评估与胰腺损伤相关的生化和形态学参数。我们将评估乙醇暴露后ADH-鹿小鼠胰腺和AR 42 J细胞中的细胞凋亡（目的2）。FAEE合酶的抑制剂或诱导剂分别减弱或增强AR 42 J细胞中FAEE的形成，将用于进一步检查内源性形成的FAEE在乙醇诱导的细胞凋亡和毒性中的作用（目的3）。实现我们的具体目标1-3应该建立FAEE在乙醇诱导的胰腺损伤中的作用，为未来的人类研究奠定基础，以开发这些参数作为乙醇诱导的胰腺损伤的早期标志物，并最终使我们在开发新的预防/治疗策略中受益，以便在胰腺发生不可逆损伤之前进行早期干预。