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

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

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. Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models. Zoological Research, 2020, 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. Assessment of mitochondrial function in metabolic dysfunction-associated fatty liver disease using obese mouse models. Zoological Research, 2020, 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

doi: 10.24272/j.issn.2095-8137.2020.051

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

Funds: This research was supported by the National Natural Science Foundation of China (Key Program: 81830071), Zhejiang Provincial Natural Science Foundation of China (LY19H040004 and Key Program: LR20H200001), and Zhejiang Provincial Health Science and Technology Plan (2015KYB238)
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  • 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。
    #Authors contributed equally to this work
  • Figure  1.  Establishment of diet-induced models of NASH

    A: Schematic of study design. Mice from two phylogenetically distant strains (B6 and D2) were randomly divided into groups (n=6 per group) and fed different diets: i.e., high-fat diet (HFD), high-fat, high-fructose, high-cholesterol diet (HFFCD), and standard diet (SD). After 4, 8, 12, and 18 weeks of feeding, mice were euthanized for subsequent experiments. B: Body weights of mice from different dietary groups (n=6 per group). C: Relative triglyceride (TG) content in different mouse groups (n=6 per group). D: Results of blood glucose and area under the curve (AUC) analysis using oral glucose tolerance test (OGTT) obtained for two strains of mice (n=6 per group). E: Blood glucose decay rate and AUC analysis of insulin tolerance test (ITT) results for two strains of mice (n=6 per group). F: Liver tissue pathological analysis using H&E staining (200× magnification) at different feeding time points. Scale bar: 25 μm. MAFLD activity scores were evaluated for each mouse (<3, no NASH; 3-5, borderline status; and >5, NASH). Red arrows indicate hepatocytes with ballooning degeneration. Yellow arrows indicate hepatic steatosis. Blue arrows indicate inflammatory cell infiltration. Data are means±SEM. *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.0001. HFD: High-fat diet; HFFCD: High-fat, high-fructose, high-cholesterol diet; SD: Standard diet.

    Figure  2.  Oxidative stress and antioxidant markers during NASH progression

    A: 8-Hydroxy-2′-deoxyguanosine (8-OHdG) levels in mouse liver tissue homogenates (n=6 per group). B: Protein carbonylation was measured using anti-DNP in liver tissues of mice (n=3 per group) fed HFD and HFFCD for 18 weeks. VDAC was used as internal control. Data are means±SEM. *: P<0.05; **: P<0.01; ***: P<0.001. HFD: High-fat diet; HFFC: High-fat, high-fructose, high-cholesterol diet; SD: Standard diet.

    Figure  3.  Hepatic mitochondrial function during NASH progression

    A: Rates of oxygen fluxes in HFD-, HFFCD-, and SD-fed mice (n=6 per group) after 4, 8, 12, and 18 weeks of feeding. CI: respiration related to combined complex I activity, measured by presence of glutamate and malate; CII: respiration related to complex II activity, measured by presence of succinate; CI + II (state 3): respiration related to combined complex I and II activity, measured by presence of glutamate, malate, and succinate; Oligo (state o): uncoupled mitochondrial respiration, measured after adding oligomycin; FCCP (state u): maximum oxygen consumption, measured after adding FCCP. B: Evaluation of mitochondrial coupling using respiratory control ratio (RCR), defined as state 3/state o ratio. C: Evaluation of proton leakage using leak control ratio (LCR), defined as state o/state u ratio. D: Respiratory chain supercomplexes in HFD-, HFFCD-, and SD-fed mice (n=3 per group). Complexes I–V were probed in blue native PAGE-separated liver tissue lysates with antibodies against Grim19, SDHA, UQCRC2, COXI, and ATP5A, respectively. SC: Supercomplex. E: In-gel enzymatic activities of mitochondrial respiratory chain complexes I, II, IV, and V in HFD-, HFFCD-, and SD-fed mice (n=3 per group). SC: Supercomplex. Data are means±SEM. *: P<0.05; **: P<0.01; ***: P<0.001. HFD: High-fat diet; HFFCD: High-fat, high-fructose, high-cholesterol diet; SD: Standard diet.

    Figure  4.  Hepatic transcriptome profiling during NASH progression

    A: Principal component analysis of data obtained for different groups (n=5 per group) at different time points. B: Number of differentially expressed genes (DEGs) in different groups at different time points. C: Up-regulated pathways associated with inflammatory responses in different groups at different time points. D: Pathways associated with oxidative stress in different groups at different time points. E: Pathways associated with mitochondrial function in different groups at different time points. F: Heatmap showing DEGs encoding transcription factors affecting mitochondrial biogenesis. G: Simulation of four gene models using four possible gene expression trends (continuous rising; continuous falling; falling and then rising; and rising and then falling) to identify involved mitochondrial genes. HFD: High-fat diet; HFFCD: High-fat, high-fructose, high-cholesterol diet; SD: Standard diet.

    Figure  5.  Hepatic transcriptome analysis of public human NASH dataset

    A: Principal component analysis of extracted data for four comparison groups (Obese relative to NC (Obese/NC), NAFL relative to NC (NAFL/NC), NASH relative to NC (NASH/NC), NASH relative to NAFL (NASH/NAFL)). B: Number of differentially expressed genes (DEGs) in each comparison group. C: KEGG pathway analysis of DEGs in each comparison group. D: Heatmap showing DEGs encoding transcription factors affecting mitochondrial biogenesis.

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  • 收稿日期:  2020-03-11
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