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首页> 外文期刊>Alcohol >Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins.
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Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins.

机译：酒精性脂肪肝的分子机制：固醇调节元件结合蛋白的作用。

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Alcoholic fatty liver is the earliest and most common response of the liver to alcohol in heavy alcohol use, and it may be a precursor of more severe forms of liver injury. We and colleagues in our laboratory found that in two rat hepatoma cell lines, H4IIEC3 and McA-RH7777, ethanol markedly induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter through increased levels of mature SREBP-1 protein. Whereas inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells, supporting the idea that the effect is likely mediated by acetaldehyde. Consistent with these in vitro findings, consumption of a low-fat diet with ethanol by mice for 4 weeks resulted in a significant increase in the abundance of the mature (active) form of hepatic SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of lipogenic genes as well as the accumulation of triglyceride in the livers. Taken together, these findings seem to indicate that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver. We and colleagues in our laboratory further studied the mechanisms of ethanol activation of SREBP-1 by identifying a new target of ethanol, adenosine 5'-monophosphate (AMP)-activated protein kinase. Our study results demonstrated that the effect of ethanol on SREBP-regulated promoter activation was mediated, at least in part, through inhibition of AMP-activated protein kinase. Consistent with this hypothesis, chronic ethanol feeding (4 weeks) resulted in a significantly reduced activity and protein level of AMP-activated protein kinase and increased acetyl coenzyme A carboxylase activity in the mouse livers.
机译：酒精性脂肪肝是重度使用酒精后肝脏对酒精的最早且最常见的反应，它可能是更严重形式的肝损伤的先兆。我们和我们实验室的同事发现，在两种大鼠肝癌细胞系H4IIEC3和McA-RH7777中，乙醇通过增加成熟SREBP-1蛋白的水平显着诱导了固醇调节元件结合蛋白（SREBP）调控的启动子的转录。 4-甲基吡唑对乙醇氧化的抑制作用阻止了该作用，而醛脱氢酶抑制剂氰胺增强了肝癌细胞中乙醇的作用，支持了这种作用可能是由乙醛介导的想法。与这些体外研究结果一致，小鼠食用乙醇低脂饮食4周导致肝SREBP-1成熟（活性）形式的丰度大大增加。乙醇喂养对SREBP-1的激活与脂肪生成基因的表达增加以及肝脏中甘油三酸酯的积累有关。综上所述，这些发现似乎表明乙醇的代谢通过激活SREBP-1来增加肝脂肪的生成，并且乙醇的这种作用可能有助于酒精性脂肪肝的发展。我们和我们实验室的同事通过鉴定乙醇的新靶标腺苷5'-单磷酸酯（AMP）活化的蛋白激酶，进一步研究了乙醇活化SREBP-1的机制。我们的研究结果表明，乙醇对SREBP调节的启动子活化的影响至少部分是通过抑制AMP活化的蛋白激酶介导的。与此假设相一致，慢性乙醇喂养（4周）导致小鼠肝脏中AMP激活的蛋白激酶的活性和蛋白水平显着降低，并且乙酰辅酶A羧化酶活性升高。

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