CHRONIC ALCOHOLISM AND LIVER ENERGY AND LIPID METABOLISM

我们实验室的长期目标是：1）研究 慢性酒精摄入对肝脏能量代谢的影响， 2)确定乙醇是否引起能量状态的改变， 肝组织有助于不可逆阶段的发展 酒精相关的肝损伤 在本提案中， 描述肝脏能量代谢中乙醇相关的变化， 发生在1）分子水平，2）分子水平和3） 在肝小叶不同区域的肝细胞中。 线粒体。 在上一个赠款期内完成的研究 研究表明，大鼠长期饮用乙醇导致 在蛋白质合成的显着改变编码的蛋白质 线粒体基因组 据确定，翻译是压抑 这是由于线粒体水平的降低。 很可能 病变是线粒体蛋白质浓度的降低 因为在来自乙醇喂养线粒体中核糖体RNA含量是正常的 大鼠 在本提案中，包括实验，以确定是否 线粒体蛋白水平降低。 其他研究将确定 哪部分机制产生了完整的线粒体 核糖体受到乙醇消耗的影响。 分子。 线粒体ATP合酶是线粒体膜上的一种复合物， 慢性乙醇对氧化磷酸化系统的不利影响 消费 抑郁症的一种可能性是 与磷脂的相互作用，需要维持其 活动 研究旨在确定线粒体是否 磷脂，心磷脂，是一个必要的组成部分，充分积极的 酶复合物 调查之后将进行研究， 确定乙醇是否引起酰基链组成的改变 心磷脂的减少解释了ATP活性的降低 合酶复合体 肝细胞。 在上一个赠款期间进行的观察表明， 肝小叶的低氧张力抑制了肝脏能量 代谢更多的乙醇消费者比对照人群。 实验的目的是更详细地探讨这一现象 利用全肝肝细胞，以及来自门静脉周围和 肝小叶的静脉周围区域。 磷NMR光谱将 在后面的研究中大量使用。

The long range objectives of our laboratory are to 1) investigate the effects of chronic ethanol consumption on hepatic energy metabolism and 2) determine if ethanol-elicited alterations in the energy state of hepatic tissue contribute to the development of the irreversible stages of alcohol-related liver damage. In this proposal studies are described to characterize ethanol-related changes in hepatic energy metabolism that occur at 1) the molecular level, 2) the level of the mitochondrion and 3) in hepatocytes from different regions of the liver lobule. Mitochondrial. Studies completed during the past granting period demonstrated that chronic ethanol consumption in rats resulted in significant alterations in the synthesis of proteins encoded by the mitochondrial genome. It was established that translation was depressed due to a decrease in the level of mitoribosomes. It is likely that the lesion is a depression in the concentration of mitoribosomal proteins since ribosomal RNA content is normal in mitochondria from ethanol-fed rats. In this proposal experiments are included to establish whether mitoribosomal protein levels are depressed. Other studies will determine which portion of the mechanism giving rise to the intact mitochondrial ribosome is affected by ethanol consumption. Molecular. The mitochondrial ATP synthase is one of the complexes of the oxidative phosphorylation system adversely affected by chronic ethanol consumption. One possibility for its depression are alterations in interactions with phospholipids, required for maintenance of its activity. Studies are designed to establish whether the mitochondrial phospholipid, cardiolipin, is an obligatory component of the fully active enzyme complex. This investigation will be followed by studies to determine if ethanol-elicited alterations in the acyl chain composition of cardiolipin explain some of the decreases in the activity of the ATP synthase complex. Hepatocyte. Observations made in the last granting period demonstrate that low oxygen tension in the liver lobule depresses hepatic energy metabolism more in ethanol consumers than in control populations. Experiments are designed to explore this phenomenon in more detail utilizing whole liver hepatocytes, and those from both the periportal and perivenous region of the liver lobule. Phosphorus NMR spectroscopy will be utilized heavily in these latter studies.