Fatty liver is associated with impaired activity of PPARγ-coactivator 1α (PGC1α) and mitochondrial biogenesis in mice
Fatty liver is associated with impaired activity of PPARγ-coactivator 1α (PGC1α) and mitochondrial biogenesis in mice
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DOI：
10.1038/labinvest.2011.55
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发表时间：
2011-07-01
影响因子：
5
通讯作者：
Tirosh, Oren
中科院分区：
文献类型：
--
作者：
Aharoni-Simon, Michal;Hann-Obercyger, Michal;Tirosh, Oren
越来越多的证据表明，线粒体在非酒精性脂肪性肝病（NAFLD）中起着关键作用。C57 BL/6 J小鼠喂食胆碱缺乏、乙硫氨酸补充（CDE）饮食。组织学研究表明，在喂食CDE饲料14天的小鼠中，高达90%的肝细胞中存在脂肪空泡蓄积。此外，还观察到线粒体水平降低以及超氧化物自由基水平升高，表明肝细胞中氧化应激升高。过夜禁食后，CDE喂养小鼠肝脏中的ATP水平降低。与对照肝脏相比，这伴随着过氧化物酶体增殖物激活受体-γ共激活因子1 α（PGC 1 α）mRNA水平的补偿性显著增加。然而，CDE处理的小鼠中PGC 1 α蛋白水平降低。此外，线粒体生物合成基因核呼吸因子1（NRF-1）、线粒体转录因子A（TFAM）、线粒体转录因子B1（TFB 1 M）和线粒体转录因子B2（TFB 2 M）的表达均受PGC 1 α活性调节，在禁食CDE处理的小鼠中保持不变。这些结果表明PGC 1 α的活性受损。染色质免疫沉淀分析进一步证实了受损的活性，这表明在喂食CDE饮食的小鼠中，PGC 1 α与含有NRF-1和NRF-2反应元件的启动子的相互作用降低。还观察到PGC 1 α激活致炎基因磷酸烯醇丙酮酸羧激酶表达的能力降低。这项研究首次证明，脂肪变性肝脏中线粒体生物合成减弱与PGC 1 α生物活性受损相关。实验室调查（2011）91，1018-1028; doi：10.1038/labinvest.2011.55; 2011年4月4日在线发表
Accumulating evidence indicates that mitochondria have a key role in non-alcoholic fatty liver disease (NAFLD). C57BL/6J mice were fed a choline-deficient, ethionine-supplemented (CDE) diet. Histological studies demonstrated accumulation of fat vacuoles in up to 90% of hepatocytes in mice fed the CDE diet for 14 days. In addition, a decrease in mitochondrial levels, together with an increase in superoxide radicals' levels were observed, indicating elevation of oxidative stress in hepatocytes. ATP levels were decreased in livers from CDE-fed mice after overnight fasting. This was accompanied by a compensative and significant increase in peroxisome-proliferator-activated receptor-gamma coactivator 1 alpha (PGC1 alpha) mRNA levels in comparison to control livers. However, there was a reduction in PGC1 alpha protein levels in CDE-treated mice. Moreover, the expression of mitochondrial biogenesis genes nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 (TFB1M) and mitochondrial transcription factor B2 (TFB2M), which are all regulated by PGC1 alpha activity, remained unchanged in fasted CDE-treated mice. These results indicate impaired activity of PGC1 alpha. The impaired activity was further confirmed by chromatin immunoprecipitation analysis, which demonstrated decreased interaction of PGC1 alpha with promoters containing NRF-1 and NRF-2 response elements in mice fed the CDE diet. A decrease in PGC1 alpha ability to activate the expression of the gluconeogenic gene phosphoenol-pyruvate carboxykinase was also observed. This study demonstrates, for the first time, that attenuated mitochondrial biogenesis in steatotic livers is associated with impaired biological activity of PGC1 alpha. Laboratory Investigation (2011) 91, 1018-1028; doi:10.1038/labinvest.2011.55; published online 4 April 2011