目的:非酒精性脂肪性肝病(NAFLD)是最常见的慢性肝病,与肝脏和心血管疾病的风险增加以及死亡率相关。NAFLD可以从单纯性肝脂肪变性发展为非酒精性脂肪性肝炎(NASH)。然而,诱发这一进展的机制仍未定义。值得注意的是,肝线粒体功能障碍是NASH患者的常见表现.由于缺乏合适的实验动物模型,尚未评估这种线粒体功能障碍是否在NASH的发展中起致病作用.
方法:为了确定明确定义的线粒体功能障碍在基线和饮食挑战期间对肝脏生理的影响,采用C57BL/6J-mt(FVB/N)小鼠。先前已报道这种再生近交系表现出线粒体呼吸降低,可能与线粒体ATP合酶蛋白8(mt-ATP8)的非同义基因变异(nt7778G/T)有关。
结果:在基线条件下,C57BL/6J-mt(FVB/N)小鼠表现出肝线粒体功能障碍,其特征是ATP产生减少和活性氧(ROS)形成增加。此外,影响脂质代谢的基因差异表达,这些动物的肝脏甘油三酯和胆固醇水平发生了变化,各种酰基肉碱被改变了,指向受损的线粒体肉碱穿梭。然而,在十二个月的时间里,未观察到自发性肝脂肪变性或炎症。另一方面,在蛋氨酸和胆碱缺乏饮食或西式饮食的饮食挑战,C57BL/6J-mt(FVB/N)小鼠发展为以脂质积累为特征的加重脂肪性肝炎,肝细胞膨胀和免疫细胞浸润。
结论:我们在线粒体多态性与肝脏线粒体功能障碍相关的小鼠中观察到明显的代谢改变。然而,第二次打击,比如饮食压力,需要引起肝脏脂肪变性和炎症。这项研究表明肝线粒体功能障碍在实验性NASH的发展中的致病作用。
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH.
METHODS: To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mt(FVB/N) mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8).
RESULTS: At baseline conditions, C57BL/6J-mt(FVB/N) mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mt(FVB/N) mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells.
CONCLUSIONS: We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.