A Combination of Mitochondrial Oxidative Stress and Excess Fat/Calorie Intake Accelerates Steatohepatitis by Enhancing Hepatic CC Chemokine Production in Mice.
A Combination of Mitochondrial Oxidative Stress and Excess Fat/Calorie Intake Accelerates Steatohepatitis by Enhancing Hepatic CC Chemokine Production in Mice.
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DOI：
10.1371/journal.pone.0146592
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Inagaki Y
中科院分区：
文献类型：
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作者：
Moro T;Nakao S;Sumiyoshi H;Ishii T;Miyazawa M;Ishii N;Sato T;Iida Y;Okada Y;Tanaka M;Hayashi H;Ueha S;Matsushima K;Inagaki Y
线粒体氧化应激被认为是包括肝脏在内的各种器官中纤维化的关键加速剂。然而，氧化应激的产生和肝纤维化的进展可能仅仅代表了原发性疾病引起的肝细胞损伤的独立后果。由于缺乏适当的实验模型来评估氧化应激的唯一影响，实际上还不知道这种应激是否与肝纤维化的进展有因果关系。在这里，我们研究了线粒体活性氧（ROS）对高脂肪/高热量饮食诱导的脂肪性肝炎的发展的直接影响Tet-mev-1小鼠，其中突变的琥珀酸脱氢酶转基因损害线粒体电子传递，并产生过量的ROS响应于多西环素管理。连续给予含有多西环素的水的野生型和Tet-mev-1小鼠随后在大约1或2岁时喂食正常食物或无胆固醇的高脂肪/高蔗糖饮食4个月。组织学检查表明，无论是在Tet-mev-1小鼠中诱导的线粒体ROS，还是单独用高脂肪/高蔗糖饮食喂养野生型动物，都不会引起显著的肝纤维化。只有当Tet-mev-1小鼠喂食高脂肪/高糖饮食时，它才诱导肝细胞中的脂质过氧化反应并增强肝脏CC趋化因子的表达。这些事件伴随着CCR 5阳性细胞浸润增加和肌成纤维细胞活化，导致广泛的肝纤维化。有趣的是，线粒体ROS和过量脂肪/卡路里摄入对肝纤维化的这种组合效应仅在2岁的Tet-mev-1小鼠中观察到，而在1岁的动物中没有观察到。总的来说，这些结果表明，线粒体ROS与过量的脂肪/卡路里摄入相结合，通过增强老年动物中CC趋化因子的产生来加速肝纤维化。我们提供了一个很好的实验模型来探索高脂肪/热量摄入如何增加线粒体适应受损的老年人对非酒精性脂肪性肝炎的易感性。
Mitochondrial oxidative stress is considered as a key accelerator of fibrosis in various organs including the liver. However, the production of oxidative stress and progression of liver fibrosis may merely represent the independent consequences of hepatocellular injury caused by the primary disease. Because of a lack of appropriate experimental models to evaluate the sole effects of oxidative stress, it is virtually unknown whether this stress is causatively linked to the progression of liver fibrosis. Here, we examined the direct effects of mitochondrial reactive oxygen species (ROS) on the progression of high fat/calorie diet-induced steatohepatitis using Tet-mev-1 mice, in which a mutated succinate dehydrogenase transgene impairs the mitochondrial electron transport and generates an excess amount of ROS in response to doxycycline administration. Wild type and Tet-mev-1 mice that had been continuously given doxycycline-containing water were subsequently fed either normal chow or a cholesterol-free high-fat/high-sucrose diet for 4 months at approximately 1 or 2 years of age. Histopathological examinations indicated that neither the mitochondrial ROS induced in Tet-mev-1 mice nor the feeding of wild type animals with high-fat/high-sucrose diet alone caused significant liver fibrosis. Only when the Tet-mev-1 mice were fed a high-fat/high-sucrose diet, it induced lipid peroxidation in hepatocytes and enhanced hepatic CC chemokine expression. These events were accompanied by increased infiltration of CCR5-positive cells and activation of myofibroblasts, resulting in extensive liver fibrosis. Interestingly, this combinatorial effect of mitochondrial ROS and excess fat/calorie intake on liver fibrosis was observed only in 2-year-old Tet-mev-1 mice, not in the 1-year-old animals. Collectively, these results indicate that mitochondrial ROS in combination with excess fat/calorie intake accelerates liver fibrosis by enhancing CC chemokine production in aged animals. We have provided a good experimental model to explore how high fat/calorie intake increases the susceptibility to nonalcoholic steatohepatitis in aged individuals who have impaired mitochondrial adaptation.