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

基本信息

批准号：
7184042
负责人：
BHUPENDRA S KAPHALIA
金额：
$ 1.51万
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：
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/7184042
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

项目摘要

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）：胰腺炎是导致高死亡率和发病率的酗酒者的主要健康问题，在胆道导管疾病之后，慢性酒精滥用是慢性胰腺炎的第二个主要原因。但是，酒精引起的胰腺炎的机制知之甚少。酒精脱氢酶（ADH）催化乙醇的氧化代谢在胰腺中可以忽略不计，而乙醇对脂肪酸乙基酯（FAEES）的非氧化代谢（faee）的非氧化代谢似乎是faee Synthase催化的，这似乎是乙醇滥用的主要机制。令人惊讶的是，关于内源形成的FAEES在乙醇引起的胰腺炎中的作用知之甚少。根据我们的初步研究表明，与ADH鹿型鹿小鼠相比，肝脏ADH缺乏症（ADH-）鹿的胰腺中FAEE水平增加了14倍，与ADH型鹿小鼠相比，与剂量和时间依赖的剂量和时间依赖性的剂量和时间相关的细胞对乙醇的细胞相比，乙醇中的人乙醇（Hep）均缺乏人乙醇（Hep））（培养，我们假设增加FAEES是乙醇引起的胰腺炎的触发事件，而FAEES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，在培养物中，在大鼠胰腺肿瘤（AR42J）细胞中形成了FAEES。因此，为了研究内源形成的粪便的毒性潜力并阐明了它们在乙醇诱导的胰腺损伤中的作用，我们将使用ADH-DEER小鼠和AR42J细胞。在AIM 1中，我们将以剂量和时间依赖性的方式来确定乙醇暴露后阿德氏小鼠血浆和胰腺中的FAEES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-DEER小鼠胰腺和AR42J细胞中的凋亡（AIM 2）。 FAEE合酶的抑制剂或诱导剂分别减弱或增强AR42J细胞中FAEES的形成，以进一步研究内源性形成的FAEES在乙醇诱导的细胞凋亡和毒性中的作用（AIM 3）。实现我们的特定目标1-3应该确定faee在乙醇引起的胰腺损伤中的作用，为未来的人类研究奠定基础，以将这些参数作为乙醇引起的胰腺损伤的早期标记，并最终使我们受益于我们在不可逆地进行胰腺造成不可逆性损害之前开发新的预防/治疗策略。