Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice
Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice
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DOI：
10.3390/cancers12061407
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发表时间：
2020-06-01
期刊：
影响因子：
5.2
通讯作者：
Dufour, Jean-Francois
中科院分区：
文献类型：
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作者：
Guarino, Maria;Kumar, Pavitra;Dufour, Jean-Francois
非酒精性脂肪性肝病（NAFLD）导致脂肪性肝炎（NASH）、纤维化和肝细胞癌。对于久坐不动的患者，结合运动和饮食改变的生活方式干预是治疗的基石。然而，当饮食改变失败时，单独运动的好处是不确定的。我们质疑在胆碱缺乏、高脂饮食（CD-HFD）小鼠模型中，单独运动是否能阻止NASH和肿瘤发生的进展。雄性C57 B1/6 N小鼠接受对照饮食或CD-HFD 12周。将CD-HFD小鼠进一步随机分组，进行8周的久坐（SED）或跑步机运动（EXE）。CD-HFD 12周产生NAFL。20周后，SED小鼠出现NASH和肝腺瘤。运动可减缓NASH的进展。与SED肝脏相比，EXE肝脏显示出较低的甘油三酯和肿瘤坏死因子-α表达、较少的纤维化、较少的气球样变和较低的NAFLD活动评分。血浆转氨酶和甘油三酯较低。运动激活AMP激活蛋白激酶（AMPK），抑制mTORC 1，降低S6磷酸化，减少肝细胞腺瘤。运动激活自噬，增加LC 3-II/LC 3-I和磷酸化PTEN诱导的激酶的线粒体募集。因此，运动减弱了从NAFL到NASH的转变，改善了NAFLD的生物化学和组织学参数，并阻碍了与AMPK信号传导的增强激活相关的纤维化和肿瘤发生的进展，并有利于肝脏自噬。我们的工作支持运动的好处独立于饮食变化。
Non-alcoholic fatty liver disease (NAFLD) leads to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. For sedentary patients, lifestyle interventions combining exercise and dietary changes are a cornerstone of treatment. However, the benefit of exercise alone when dietary changes have failed is uncertain. We query whether exercise alone arrests the progression of NASH and tumorigenesis in a choline-deficient, high-fat diet (CD-HFD) murine model. Male C57Bl/6N mice received a control diet or CD-HFD for 12 weeks. CD-HFD mice were randomized further for 8 weeks of sedentariness (SED) or treadmill exercise (EXE). CD-HFD for 12 weeks produced NAFL. After 20 weeks, SED mice developed NASH and hepatic adenomas. Exercise attenuated the progression to NASH. EXE livers showed lower triglycerides and tumor necrosis factor-alpha expression, less fibrosis, less ballooning, and a lower NAFLD activity score than did SED livers. Plasma transaminases and triglycerides were lower. Exercise activated AMP-activated protein kinase (AMPK) with inhibition of mTORC1 and decreased S6 phosphorylation, reducing hepatocellular adenoma. Exercise activated autophagy with increased LC3-II/LC3-I and mitochondrial recruitment of phosphorylated PTEN-induced kinase. Therefore, exercise attenuates the transition from NAFL to NASH, improves biochemical and histological parameters of NAFLD, and impedes the progression of fibrosis and tumorigenesis associated with enhanced activation of AMPK signaling and favors liver autophagy. Our work supports the benefits of exercise independently of dietary changes.