CHRONIC ALCOHOLISM AND LIVER ENERGY AND LIPID METABOLISM

我们实验室的长期目标是：1)调查 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 肝组织在不可逆期的发展中起作用 与酒精有关的肝脏损伤。在这份提案中，描述了研究 为了描述与酒精相关的肝脏能量代谢的变化 发生在1)分子水平，2)线粒体水平和3) 在来自肝小叶不同区域的肝细胞中。 线粒体。在过去批准期内完成的研究 证明了长期饮酒会导致大鼠 编码的蛋白质合成的显著变化 线粒体基因组。事实证明，翻译受到了抑制 这是由于有丝分裂体水平的下降。很可能是因为 病变是有丝分裂体蛋白浓度的降低。 由于乙醇喂养的线粒体中核糖体RNA含量正常 老鼠。在这项建议中，包括了实验以确定 有丝分裂体蛋白水平受到抑制。其他研究将确定 产生完整线粒体的机制的哪一部分 核糖体受到乙醇消耗的影响。 分子。线粒体三磷酸腺苷合成酶是一种 慢性乙醇对氧化磷酸化系统的不利影响 消费。导致其抑郁的一种可能性是 与磷脂的相互作用，维持ITS所需的 活动。研究的目的是确定线粒体是否 磷脂，即心磷脂，是充分发挥作用的必需成分 酶复合体。在这项调查之后，将研究 确定乙醇是否引起酰基链组成的改变 心磷脂可以解释ATP活性下降的部分原因 合成酶复合体。 肝细胞。在上次批准期内所作的观察显示 肝小叶低氧分压抑制肝脏能量 与对照人群相比，乙醇消费者的新陈代谢更强。 实验旨在更详细地探索这一现象。 利用全肝肝细胞，门静脉周围和门静脉周围的肝细胞 肝小叶的静脉周围区域。磷核磁共振光谱学将 在这些后面的研究中得到了大量的利用。

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.