Mansouri A, Fromenty B, Berson A, Robin M A, Grimbert S, Beaugrand M, Erlinger S, Pessayre D
INSERM Unité 24 and Centre de Recherche de Physiopathologie Hépatique(Association Claude Bernard), Hôpital Beaujon, Clichy, France.
J Hepatol. 1997 Jul;27(1):96-102. doi: 10.1016/s0168-8278(97)80286-3.
BACKGROUND/AIMS: A 4977-base pair deletion has been detected in the hepatic mitochondrial DNA of alcoholic patients with microvesicular steatosis, a lesion ascribed to impaired mitochondrial beta-oxidation. However, only a single deletion had been looked for in this previous study, and it could not be determined whether the deletion was preexisting or acquired. Alcohol abuse increases the formation of reactive oxygen species in hepatic mitochondria. If this effect accelerates the oxidative aging of mitochondrial DNA, several other mutations would be expected.
The mtDNA region extending from nucleotide 8167 to nucleotide 14246 was screened for the presence of large mitochondrial DNA deletions in 58 alcoholic patients and 67 age-matched non-alcoholic controls. Hepatic DNA was subjected to polymerase chain reactions that amplified non-deleted and deleted mitochondrial DNA, respectively, and the boundaries of the mitochondrial DNA deletions were sequenced.
Only 3% of the non-alcoholic controls carried a mitochondrial DNA deletion, whereas 24% of all alcoholic patients and 85% of the 13 alcoholic patients with microvesicular steatosis exhibited either single or multiple 4977, 5385, 5039 and 5556-base pair mitochondrial DNA deletions. No deletion(s) were observed, however, in 13 patients with microvesicular steatosis due to other causes.
Diverse mitochondrial DNA rearrangements are observed in alcoholic patients with microvesicular steatosis. We suggest that alcohol abuse leads to premature oxidative aging of mitochondrial DNA. Hypothetically, oxidative damage to mitochondrial constituents (DNA, proteins and lipids) may favor microvesicular fat deposition.
背景/目的：在患有微泡性脂肪变性的酒精性肝病患者的肝线粒体DNA中检测到一个4977个碱基对的缺失，该病变归因于线粒体β氧化受损。然而，在之前的这项研究中仅寻找了单一的缺失，并且无法确定该缺失是预先存在的还是后天获得的。酒精滥用会增加肝线粒体中活性氧的形成。如果这种作用加速了线粒体DNA的氧化衰老，预计还会出现其他几种突变。
对58例酒精性肝病患者和67例年龄匹配的非酒精性对照者的线粒体DNA区域（从核苷酸8167延伸至核苷酸14246）进行筛查，以检测是否存在大的线粒体DNA缺失。提取肝脏DNA，分别进行聚合酶链反应，扩增未缺失和缺失的线粒体DNA，并对线粒体DNA缺失的边界进行测序。
仅3%的非酒精性对照者存在线粒体DNA缺失，而在所有酒精性肝病患者中，24%以及在13例患有微泡性脂肪变性的酒精性肝病患者中，85%表现出单个或多个4977、5385、5039和5556个碱基对的线粒体DNA缺失。然而，在13例由其他原因导致微泡性脂肪变性的患者中未观察到缺失。
在患有微泡性脂肪变性的酒精性肝病患者中观察到多种线粒体DNA重排。我们认为酒精滥用会导致线粒体DNA过早氧化衰老。据推测，线粒体成分（DNA、蛋白质和脂质）的氧化损伤可能有利于微泡性脂肪沉积。
