Begriche Karima, Igoudjil Anissa, Pessayre Dominique, Fromenty Bernard
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 481, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 750118 Paris, France.
Mitochondrion. 2006 Feb;6(1):1-28. doi: 10.1016/j.mito.2005.10.004. Epub 2006 Jan 5.
Calorie-enriched diet and lack of exercise are causing a worldwide surge of obesity, insulin resistance and lipid accretion in liver (i.e. hepatic steatosis), which can lead to steatohepatitis. Steatosis and nonalcoholic steatohepatitis (NASH) can also be induced by drugs such as amiodarone, tamoxifen and some antiretroviral drugs, including stavudine and zidovudine. There is accumulating evidence that mitochondrial dysfunction (more particularly respiratory chain deficiency) plays a key role in the physiopathology of NASH whatever its initial cause. In contrast, the mitochondrial beta-oxidation of fatty acids can be either increased (as in insulin resistance-associated NASH) or decreased (as in drug-induced NASH). However, in both circumstances, generation of reactive oxygen species (ROS) by the damaged respiratory chain can be augmented. ROS generation in an environment enriched in lipids in turn induces lipid peroxidation which releases highly reactive aldehydic derivatives (e.g. malondialdehyde) that have diverse detrimental effects on hepatocytes and other hepatic cells. In hepatocytes, ROS, reactive nitrogen species and lipid peroxidation products further impair the respiratory chain, either directly or indirectly through oxidative damage to the mitochondrial genome. This consequently leads to the generation of more ROS and a vicious cycle occurs. Mitochondrial dysfunction can also lead to apoptosis or necrosis depending on the energy status of the cell. ROS and lipid peroxidation products also increase the generation of several cytokines (TNF-alpha, TGF-beta, Fas ligand) playing a key role in cell death, inflammation and fibrosis. Recent investigations have shown that some genetic polymorphisms can significantly increase the risk of steatohepatitis and that several drugs can prevent or even reverse NASH. Interestingly, most of these drugs could exert their beneficial effects by improving directly or indirectly mitochondrial function in liver. Finding a drug, which could fully prevent oxidative stress and mitochondrial dysfunction in NASH is a major challenge for the next decade.
高热量饮食和缺乏运动正导致全球范围内肥胖、胰岛素抵抗以及肝脏脂质蓄积（即肝脂肪变性）的激增，而这可能会引发脂肪性肝炎。脂肪变性和非酒精性脂肪性肝炎（NASH）也可由诸如胺碘酮、他莫昔芬以及一些抗逆转录病毒药物（包括司他夫定和齐多夫定）等药物诱发。越来越多的证据表明，无论NASH的初始病因如何，线粒体功能障碍（尤其是呼吸链缺陷）在其病理生理过程中都起着关键作用。相比之下，脂肪酸的线粒体β氧化在胰岛素抵抗相关的NASH中可能会增强，而在药物诱导的NASH中则可能会减弱。然而，在这两种情况下，受损呼吸链产生的活性氧（ROS）都会增加。在富含脂质的环境中ROS的产生进而会诱导脂质过氧化，释放出具有多种有害作用的高反应性醛衍生物（如丙二醛），这些衍生物会对肝细胞和其他肝内细胞产生不同的有害影响。在肝细胞中，ROS、活性氮物质和脂质过氧化产物会直接或通过对线粒体基因组的氧化损伤间接进一步损害呼吸链。这进而会导致产生更多的ROS，从而形成恶性循环。线粒体功能障碍还可能导致细胞凋亡或坏死，具体取决于细胞的能量状态。ROS和脂质过氧化产物还会增加几种细胞因子（肿瘤坏死因子-α、转化生长因子-β、Fas配体）的产生，这些细胞因子在细胞死亡、炎症和纤维化中起关键作用。最近的研究表明，一些基因多态性可显著增加脂肪性肝炎的风险，并且几种药物可以预防甚至逆转NASH。有趣的是，这些药物中的大多数可能通过直接或间接改善肝脏的线粒体功能来发挥其有益作用。找到一种能够完全预防NASH中的氧化应激和线粒体功能障碍的药物是未来十年的一项重大挑战。
