Role of mitochondria in non-alcoholic fatty liver disease
Role of mitochondria in non-alcoholic fatty liver disease
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DOI：
10.1111/j.1440-1746.2006.04640.x
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Pessayre, Dominique
中科院分区：
文献类型：
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作者：
Pessayre, Dominique
线粒体功能障碍涉及从缺乏运动和过量食物摄入到胰岛素抵抗、糖尿病和非酒精性脂肪性肝炎(NASH)的三个过渡阶段。在肌肉中，缺乏运动、富含脂肪的饮食、过氧化物酶体增殖物激活受体-1(PGC-1)基因的多态性，以及可能与年龄相关的线粒体DNA(MtDNA)突变，可能会不同程度地结合它们的作用来降低PGC-1的表达、线粒体的生物发生和脂肪氧化。再加上食物摄入过多，脂肪氧化不足会导致心肌细胞脂肪堆积和细胞应激。Jun氨基末端激酶和蛋白激酶C-theta的激活触发了胰岛素受体底物的丝氨酸磷酸化和失活，并阻碍了胰岛素介导的葡萄糖转运蛋白4到质膜的转位。最初，血糖升高的趋势会增加胰岛β细胞的胰岛素分泌。高水平的血浆胰岛素可以补偿肌肉中的胰岛素抵抗，并维持正常的血糖水平。然而，最终，解偶联蛋白-2的表达增加以及可能的获得性线粒体DNA突变会抑制葡萄糖介导的三磷酸腺苷(ATP)的形成和胰岛素的分泌，从而在一些患者中导致糖尿病。高血糖和/或高胰岛素水平会导致肝脏脂肪生成，并导致肝脏脂肪变性。在脂肪充血的肝细胞中，肿瘤坏死因子-α、活性氧(ROS)、过氧亚硝酸盐和脂质过氧化产物等几个恶性循环改变了呼吸链多肽和线粒体DNA，从而部分阻断了呼吸链中的电子流动。上游呼吸链复合体的过度还原增加了线粒体ROS和过氧亚硝酸盐的形成。氧化应激增加脂质过氧化产物和细胞因子的释放，共同触发NASH的肝脏损害。
Mitochondrial dysfunction is involved in the three stages of the transition from lack of exercise and excessive food intake to insulin resistance, diabetes and non-alcoholic steatohepatitis (NASH). In muscle, lack of exercise, a fat-rich diet, a polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), and possibly age-related mitochondrial DNA (mtDNA) mutations may variously combine their effects to decrease PGC-1 expression, mitochondrial biogenesis and fat oxidation. Together with excessive food intake, insufficient fat oxidation causes fat accumulation and cellular stress in myocytes. The activation of Jun N-terminal kinase and protein kinase C-theta triggers the serine phosphorylation and inactivation of the insulin receptor substrate, and hampers the insulin-mediated translocation of glucose transporter-4 to the plasma membrane. Initially, the trend for increased blood glucose increases insulin secretion by pancreatic beta-cells. High plasma insulin levels compensate for insulin resistance in muscle and maintain normal blood glucose levels. Eventually, however, increased uncoupling protein-2 expression and possibly acquired mtDNA mutations in pancreatic beta-cells can blunt glucose-mediated adenosine triphosphate (ATP) formation and insulin secretion, to cause diabetes in some patients. High plasma glucose and/or insulin levels induce hepatic lipogenesis and cause hepatic steatosis. In fat-engorged hepatocytes, several vicious cycles involving tumor necrosis factor-alpha, reactive oxygen species (ROS), peroxynitrite, and lipid peroxidation products alter respiratory chain polypeptides and mtDNA, thus partially blocking the flow of electrons in the respiratory chain. The overreduction of upstream respiratory chain complexes increases mitochondrial ROS and peroxynitrite formation. Oxidative stress increases the release of lipid peroxidation products and cytokines, which together trigger the liver lesions of NASH.