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。通过与乙醇和酒精脱氢酶（ADH）的经典抑制剂共同处理JNK和AKT的激活。额外的抗氧化剂降低了JNK的激活。用ADH抑制作用的乙醇载荷导致GRP78 mRNA水平的下调。因此，这些发现表明，抑制乙醇代谢的第一反应使乙醇产生的氧化物和ER应激复杂化。非酒精性脂肪肝的发展与胰岛素抵抗无关，而涉及抑制SREBP-1C。这表明SREBP-1C的激活剂可能会诱导脂肪变性到脂肪性肝炎的进展。由于NF-κB抑制剂减少了脂肪变性和PPAR激动剂，然后改善了内质网应激，因此它们也可能有效地改善NAFLD.3。鱼油进食引起肝脏炎症，并诱导促炎性细胞因子，PPARS，CYP4AS和CYP2E1。鱼油含有丰富的多不饱和脂肪酸。这些发现表明，多不饱和脂肪酸在酒精和非酒精性脂肪肝病的发展中起着至关重要的作用。4。后肢卸载导致门户内毒素水平升高，但并未引起严重的肝损伤。用于后肢卸载模型的急性乙醇治疗通过TLR4信号传导引起促炎反应的灾难。