Exploratory Project: 1 Mitochondrial Phospholipid Oxidation in Alcoholic Liver

ALD是美国慢性肝病最常见的原因之一，许多 其他国家ALD代表了从酒精性脂肪变性到酒精性肝损害的广泛范围。 脂肪性肝炎（ASH）至肝硬化。ASH代表ALD光谱内的一个阶段，其特征在于 脂质在肝脏中的积累（脂肪变性）沿着炎症和不同程度的瘢痕形成 或纤维化（8）。ASH是潜在的严重疾病，因为ASH患者的疾病风险特别高 进展为肝硬化及其并发症，包括门静脉高压症、肝衰竭和肝细胞癌 癌（4，9）。 慢性乙醇消耗改变肝脏线粒体结构和功能（2-5），以及最近的工作 这表明，这种慢性乙醇相关的线粒体健康障碍也可能是负责 ROS的产生增加，这是一种导致ALD肝损伤和疾病进展的中枢异常 （6-12）。现存的中心问题是什么事件将过量饮酒与线粒体 功能障碍线粒体ROS产生的小幅增加可能导致随后的严重紊乱 以及大量ROS产生、膜电位崩溃、肿胀和细胞色素c释放（13）。这些 事件进行并导致凋亡性细胞死亡。 磷脂（氢）过氧化物的过氧化物官能团具有化学反应性，并且可以分解以形成磷脂（氢）过氧化物。 具有不同sn-2残基的各种片段化磷脂。磷脂氢过氧化物也是 游离脂肪酸氢过氧化物的来源，因此是氧化应激的早期标志物。其中一些 磷脂氧化产物在体外释放细胞色素c时破坏线粒体结构 测定。这些不仅仅是氧化的标志，因为我们发现（1）碎片化的磷脂很容易 进入细胞，原位破坏线粒体，并启动内在凋亡级联反应。

ALD is one of the most common causes of chronic liver disease in the United States, and many other countries. ALD represents a wide spectrum of liver damage ranging from alcoholic steatosis, to alcoholic steatohepatitis (ASH), to cirrhosis. ASH represents a stage within the spectrum of ALD that is characterized by the accumulation of lipid stores in the liver (steatosis) along with inflammation and different degrees of scarring or fibrosis (8). ASH is potentially serious condition, as patients with ASH are at particular risk for disease progression to cirrhosis and its complications including portal hypertension, liver failure and hepatocellular carcinoma (4, 9). Chronic ethanol consumption alters liver mitochondria structure as well as function (2-5), and recent work suggests that this chronic ethanol-related disturbance in mitochondria health might also be responsible for an increased production of ROS, a central abnormality responsible for liver injury and disease progression in ALD (6-12). The central question extant is what events link excess alcohol consumption to mitochondrial dysfunction. Small increases in mitochondrial ROS production may lead to subsequent severe derangement and massive ROS production, membrane potential collapse, swelling and cytochrome c release (13). These events proceed, and are responsible for, apoptotic cell death. The peroxide function of phospholipid (hydro)peroxides are chemically reactive and can disintegrate to form a variety of fragmented phospholipids with varied sn-2 residues. Phospholipid hydroperoxides also are the source of free fatty acid hydroperoxides, and so are early markers of oxidative stress. Some of these phospholipid oxidation products potently disrupt mitochondrial structure with cytochrome c release in in vitro assays. These are more than markers of oxidation because we find (1) that fragmented phospholipids readily enter cells, damage mitochondria in situ, and initiate the intrinsic apoptotic cascade.