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赵琼雅, 葛玲虹, 张琨, 陈海峰, 战欣欣, 杨月, 党清琳, 郑易, 周怀彬, 吕建新, 方合志. 2020: 饮食诱导的代谢相关脂肪性肝病小鼠模型中线粒体功能的评估. 动物学研究, 41(5): 539-551. DOI: 10.24272/j.issn.2095-8137.2020.051
引用本文: 赵琼雅, 葛玲虹, 张琨, 陈海峰, 战欣欣, 杨月, 党清琳, 郑易, 周怀彬, 吕建新, 方合志. 2020: 饮食诱导的代谢相关脂肪性肝病小鼠模型中线粒体功能的评估. 动物学研究, 41(5): 539-551. DOI: 10.24272/j.issn.2095-8137.2020.051
Qiong-Ya Zhao, Ling-Hong Ge, Kun Zhang, Hai-Feng Chen, Xin-Xin Zhan, Yue Yang, Qing-Lin Dang, Yi Zheng, Huai-Bin Zhou, Jian-Xin Lyu, He-Zhi Fang. 2020: Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models. Zoological Research, 41(5): 539-551. DOI: 10.24272/j.issn.2095-8137.2020.051
Citation: Qiong-Ya Zhao, Ling-Hong Ge, Kun Zhang, Hai-Feng Chen, Xin-Xin Zhan, Yue Yang, Qing-Lin Dang, Yi Zheng, Huai-Bin Zhou, Jian-Xin Lyu, He-Zhi Fang. 2020: Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models. Zoological Research, 41(5): 539-551. DOI: 10.24272/j.issn.2095-8137.2020.051

饮食诱导的代谢相关脂肪性肝病小鼠模型中线粒体功能的评估

Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models

  • 摘要: 代谢相关脂肪性肝病(MAFLD)以肝脏脂质代谢失调为特征,然而,其发生发展与线粒体功能代谢之间的关联尚无明确的结论。本研究采用高分辨率呼吸测定系统、基于蓝色天然聚丙烯酰胺凝胶电泳的凝胶内活性分析和免疫印迹分析等方法,对饮食诱导的不同程度MAFLD小鼠模型中的线粒体功能进行评估。结果显示,与常规饮食相比,饲喂高脂/高糖饮食的部分(非全部)MAFLD小鼠的肝脏线粒体呼吸能力有轻微的下降,而线粒体氧化磷酸化复合体的活性和含量保持不变,这表明在肥胖引起的MAFLD发生发展过程中,线粒体功能,尤其是氧化磷酸化功能仅受到轻微影响。此外,对肥胖相关的MAFLD小鼠和人类肝脏组织样本的转录组数据分析发现,与对照相比,线粒体相关通路仅在病理组织程度较严重的MAFLD小鼠中呈现下调,而线粒体生物发生相关的转录调节因子并无明显的改变。我们的研究结果表明,肝脏线粒体功能损伤与肥胖引起的MAFLD并不密切相关。因此,应重新考虑针对线粒体的MAFLD治疗策略。

     

    Abstract: Metabolic dysfunction-associated fatty liver disease (MAFLD) is characterized by deregulated hepatic lipid metabolism; however, the association between MAFLD development and mitochondrial dysfunction has yet to be confirmed. Herein, we employed high-resolution respirometry, blue native polyacrylamide gel electrophoresis-based in-gel activity measurement and immunoblot analysis to assess mitochondrial function in obesity-induced mouse models with varying degrees of MAFLD. Results showed a slight but significant decrease in hepatic mitochondrial respiration in some MAFLD mice compared to mice fed a standard diet. However, the activities and levels of mitochondrial oxidative phosphorylation complexes remained unchanged during obesity-induced MAFLD progression. These results suggest that mitochondrial function, particularly oxidative phosphorylation, was mildly affected during obesity-induced MAFLD development. Moreover, transcriptome profiling of mouse and human liver tissues with varying degrees of MAFLD revealed that the decreased activation of mitochondria-related pathways was only associated with MAFLD of a high histological grade, whereas the major regulators of mitochondrial biogenesis were not altered in mice or humans during MAFLD development. Collectively, our results suggest that impaired hepatic mitochondrial function is not closely associated with obesity-induced MAFLD. Therefore, therapeutic strategies targeting mitochondria for the treatment of MAFLD should be reconsidered.

     

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