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Molecular mechanisms of disturbance in cell survival system by alcohol abuse

酗酒扰乱细胞生存系统的分子机制

基本信息

批准号：
16390196
负责人：
MATSUMOTO Hiroshi
金额：
$ 8.38万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390196/
关键词：
alcohol NF-kappaB JNK Akt SREBP TLR4 polyunsaturated fatty acid NAFLD CYP2E1 PPAR NF-KappaB SREBP

项目摘要

1. Activations of JNK and Akt were enhanced by co-treatment with ethanol and a classical inhibitor of alcohol dehydrogenase (ADH). Addition of an anti- oxidant reduced the activation of JNK. Ethanol loading with ADH inhibition causes down-regulation of GRP78 mRNA levels. Therefore, these findings suggest first revelation that inhibition of ethanol metabolism complicates oxidative and ER stresses produced by ethanol..2. The development of nonalcoholic fatty liver was not associated with insulin resistance but involves suppression of SREBP-1c. This suggests an activator of SREBP-1c may induce the progression of steatosis to steatohepatitis. Since NF- κB inhibitors reduced the steatosis as well as PPAR agonists and then decreased endoplasmic reticulum stress, they may be also effective in ameliorating NAFLD.3. Fish oil feeding caused inflammation in the liver and induced proinflammatory cytokines, PPARs, CYP4As, and CYP2E1. Fish oil contains rich polyunsaturated fatty acids. These findings suggest that polyunsaturated fatty acid plays a crucial role in development of alcoholic and nonalcoholic fatty liver disease.4. Hindlimb unloading caused elevating portal endotoxin levels, but did not cause sever liver injury. Acute ethanol treatment for the hindlimb unloading model induced disturbance in proinflammmatory response via TLR4 signalling.

1. JNK和Akt的激活增强与乙醇和乙醇脱氢酶（ADH）的经典抑制剂的共同处理。抗氧化剂的加入降低了JNK的活化。乙醇负载ADH抑制引起GRP 78 mRNA水平下调。因此，这些发现首次揭示了乙醇代谢的抑制使乙醇产生的氧化和ER应激复杂化。2.非酒精性脂肪肝的发生与胰岛素抵抗无关，但涉及SREBP-1c的抑制。这表明SREBP-1c的激活剂可能诱导脂肪变性进展为脂肪性肝炎。由于NF- κB抑制剂和PPAR激动剂一样减少脂肪变性，然后减少内质网应激，因此它们也可能有效地改善NAFLD.鱼油喂养引起肝脏炎症，并诱导促炎细胞因子，PPARs，CYP 4A和CYP 2 E1。鱼油含有丰富的多不饱和脂肪酸。这些结果表明，多不饱和脂肪酸在酒精性和非酒精性脂肪肝的发生发展中起着至关重要的作用.后肢去负荷引起门静脉内毒素水平升高，但未引起严重的肝损伤。急性乙醇治疗后肢卸载模型诱导的干扰，通过TLR 4信号的促炎反应。