...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Alcohol >Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice.
【24h】

Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice.

机译：乙醇诱发肝酒精脱氢酶缺乏症的鹿小鼠乙醇和肝，胰腺损伤的代谢基础。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Alcoholic liver disease (ALD) and alcoholic pancreatitis (AP) are major diseases causing high mortality and morbidity among chronic alcohol abusers. Neutral lipid accumulation (steatosis) is an early stage of ALD or AP and progresses to inflammation and other advanced stages of diseases in a subset of chronic alcohol abusers. However, the mechanisms of alcoholic steatosis leading to ALD and AP are not well understood. Chronic alcohol abuse impairs hepatic alcohol dehydrogenase (ADH, a major enzyme involved in ethanol oxidative metabolism) and facilitates nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol). These esters are implicated in the pathogenesis of various alcoholic diseases and shown to cause hepatocellular and pancreatitis-like injury. Ethanol exposure is known to increase synthesis of FAEEs by several-fold in the livers and pancreata of rats pretreated with hepatic ADH inhibitor. Therefore, studies were undertaken to evaluate hepatocellular and pancreatic injury in hepatic ADH-deficient (ADH(-)) deer mice versus ADH-normal (ADH(+)) deer mice fed ethanol (4% wt/vol) via Lieber-DeCarli liquid diet for 60 days. A significant mortality was found in ethanol-fed ADH(-) deer mice (11 out of 18) versus ADH(+) deer mice (1 out of 16); most of the deaths occurred during the first 2 weeks of ethanol exposure. The surviving animals, sacrificed at the end of 60th day, showed distinct changes in hepatic and pancreatic histology and several-fold increases in nonoxidative metabolism of ethanol in ethanol-fed ADH(-) versus ADH(+) deer mice. Extensive vacuolization with displacement or absence of nucleus in some hepatocytes, and significant increase in hepatic neutral lipids were found in ethanol-fed ADH(-) versus ADH(+) deer mice. Ultrastructural changes showed perinuclear space, edema, presence of apoptotic bodies and disintegration, and/or dilatation of endoplasmic reticulum (ER) in the pancreata of ethanol-fed ADH(-) deer mice. FAEE levels weresignificantly higher in ADH(-) versus ADH(+) deer mice, approximately four-fold increases in the livers and seven-fold increases in the pancreata. Ethyl esters of oleic, linoleic, and arachidonic acids were the major FAEEs detected in ethanol-fed groups. The role of FAEEs in pancreatic lysosomal fragility is reflected by higher activity of cathepsin B (five-fold) in ethanol-fed ADH(-) versus ADH(+) deer mice. Although the present studies clearly indicate a metabolic basis of ethanol-induced hepatic and pancreatic injury, detailed dose- and time-dependent toxicity studies in this ADH(-) deer mouse model could reveal further a better understanding of mechanism(s) of ethanol-induced hepatic and pancreatic injuries.
机译：酒精性肝病（ALD）和酒精性胰腺炎（AP）是引起慢性酒精滥用者高死亡率和高发病率的主要疾病。中性脂质蓄积（脂肪变性）是ALD或AP的早期阶段，在一部分慢性饮酒者中会发展为炎症和其他疾病晚期阶段。然而，酒精性脂肪变性导致ALD和AP的机制尚不十分清楚。长期滥用酒精会损害肝酒精脱氢酶（ADH，一种参与乙醇氧化代谢的主要酶），并促进乙醇的非氧化代谢为脂肪酸乙酯（FAEE，乙醇的非氧化代谢物）。这些酯与多种酒精性疾病的发病机制有关，并显示可引起肝细胞和胰腺炎样损伤。已知乙醇暴露会增加用肝ADH抑制剂预处理的大鼠的肝脏和胰腺中FAEE的合成数倍。因此，进行了研究，以评估通过利伯-德卡利液体喂养乙醇（4％wt / vol）的ADH缺乏（ADH（-））鹿肝小鼠与ADH正常（ADH（+））鹿小鼠的肝细胞和胰腺损伤饮食60天。在以乙醇喂养的ADH（-）鹿小鼠（18只中的11只）与ADH（+）鹿小鼠（16只中的1只）中发现了显着的死亡率。大多数死亡发生在乙醇暴露的前2周。存活的动物在第60天结束时被处死，在以乙醇喂养的ADH（-）相对于ADH（+）鹿小鼠中，肝脏和胰腺的组织学表现出明显的变化，乙醇的非氧化代谢增加了数倍。在乙醇喂养的ADH（-）相比于ADH（+）的鹿小鼠中，发现一些肝细胞中大量空泡发生位移或没有细胞核，并且肝中性脂质显着增加。超微结构变化显示乙醇喂养的ADH（-）鹿小鼠胰腺中核周空间，水肿，凋亡小体的存在和崩解和/或内质网（ER）扩张。与ADH（+）鹿相比，ADH（-）小鼠的FAEE水平显着更高，肝脏约增加4倍，胰腺约增加7倍。油酸，亚油酸和花生四烯酸乙酯是在乙醇喂养组中检测到的主要FAEE。 FAEEs在胰腺溶酶体脆弱性中的作用反映在由乙醇喂养的ADH（-）相对于ADH（+）鹿小鼠中组织蛋白酶B（5倍）的较高活性。尽管目前的研究清楚地表明了乙醇诱发的肝和胰腺损伤的代谢基础，但是在该ADH（-）鹿小鼠模型中进行的详细的剂量依赖性和时间依赖性毒性研究可以揭示出对乙醇-机理的进一步了解。诱发肝和胰腺损伤。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号