Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice.
Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice.
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DOI：
10.1042/bj20131433
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发表时间：
2014-07-15
期刊：
影响因子：
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通讯作者：
Bailey SM
中科院分区：
文献类型：
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作者：
Betancourt AM;King AL;Fetterman JL;Millender-Swain T;Finley RD;Oliva CR;Crowe DR;Ballinger SW;Bailey SM
非酒精性脂肪性肝病（NAFLD）涉及肝脏代谢的显著变化，其特征在于氧化应激、脂质蓄积和纤维化。线粒体功能障碍和生物能量缺陷也有助于NAFLD。在此，我们研究了mtDNA的差异是否影响NAFLD。为了确定线粒体和核基因组在NAFLD中的作用，给线粒体-核交换（MNX）小鼠喂食致动脉粥样硬化饮食。MNX小鼠具有来自C57 BL/6 J小鼠的mtDNA，其核背景为C3 H/HeN，反之亦然。将来自MNX小鼠的结果与喂食对照或致动脉粥样硬化饮食的野生型C57 BL/6 J和C3 H/HeN小鼠进行比较。当喂食致动脉粥样硬化饮食时，与含有C3 H/HeN核基因组的小鼠相比，具有C57 BL/6 J核基因组的小鼠发生更多的大脂肪变性、炎症和纤维化。这些变化与野生型小鼠中炎症和纤维化基因表达的平行改变相关，在MNX小鼠中具有中等反应。当喂食致动脉粥样硬化饮食时，具有C57 BL/6 J核基因组的小鼠具有增加的状态4呼吸，而MNX小鼠具有降低的状态3呼吸和RCR。复合物IV活性和大多数线粒体生物发生基因在喂食致动脉粥样硬化饮食的C57 BL/6 J核或线粒体基因组或两者的小鼠中增加。这些结果揭示了线粒体和核基因组之间的新的相互作用，并支持mtDNA影响线粒体功能和NAFLD中涉及的代谢途径的概念。
Nonalcoholic fatty liver disease (NAFLD) involves significant changes in liver metabolism characterized by oxidative stress, lipid accumulation, and fibrogenesis. Mitochondrial dysfunction and bioenergetic defects also contribute to NAFLD. Herein, we examined whether differences in mtDNA influence NAFLD. To determine the role of mitochondrial and nuclear genomes in NAFLD, Mitochondrial-Nuclear eXchange (MNX) mice were fed an atherogenic diet. MNX mice have mtDNA from C57BL/6J mice on a C3H/HeN nuclear background and vice versa. Results from MNX mice were compared to wild-type C57BL/6J and C3H/HeN mice fed a control or atherogenic diet. Mice with the C57BL/6J nuclear genome developed more macrosteatosis, inflammation, and fibrosis compared with mice containing the C3H/HeN nuclear genome when fed the atherogenic diet. These changes were associated with parallel alterations in inflammation and fibrosis gene expression in wild-type mice, with intermediate responses in MNX mice. Mice with the C57BL/6J nuclear genome had increased State 4 respiration, whereas MNX mice had decreased State 3 respiration and RCR when fed the atherogenic diet. Complex IV activity and most mitochondrial biogenesis genes were increased in mice with the C57BL/6J nuclear or mitochondrial genome, or both fed the atherogenic diet. These results reveal new interactions between mitochondrial and nuclear genomes and support the concept that mtDNA influences mitochondrial function and metabolic pathways implicated in NAFLD.