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。酒精性肝病代表了从酒精性脂肪变性到酒精性脂肪肝的多种肝脏损害。 脂肪性肝炎(ASH)，到肝硬变。火山灰代表ALD光谱中的一个阶段，其特征是 肝脏中脂肪堆积(脂肪变性)，伴随炎症和不同程度的瘢痕形成 或纤维化(8例)。ASH是一种潜在的严重疾病，因为ASH患者的患病风险特别高 进展为肝硬变及其并发症，包括门脉高压、肝功能衰竭和肝细胞癌 癌(4、9)。 慢性酒精摄入改变肝脏线粒体结构和功能(2-5)，以及最近的研究 提示这种与酒精有关的线粒体健康慢性紊乱可能也是导致 ROS的产生增加，这是一种导致ALD肝脏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联系起来 功能障碍。线粒体ROS产量的微小增加可能会导致随后的严重紊乱 ROS大量产生，膜电位崩塌、肿胀、细胞色素c释放(13)。这些 这些事件继续进行，并对细胞的凋亡负责。 磷脂(氢)过氧化物的过氧化作用是化学反应的，可以分解形成 含有不同sn-2残基的各种碎片化磷脂。磷脂过氧化氢也是 游离脂肪酸过氧化氢的来源，因此是氧化应激的早期标志。其中一些 磷脂氧化产物在体外通过释放细胞色素c来破坏线粒体结构 化验。这些不仅仅是氧化的标志，因为我们发现(1)碎裂的磷脂很容易 进入细胞，原位损伤线粒体，启动固有的细胞凋亡级联反应。

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.