Energy metabolism adaptations and gene expression reprogramming in a cellular MAFLD model
Energy metabolism adaptations and gene expression reprogramming in a cellular MAFLD model
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DOI：
10.1101/2021.11.08.467719
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发表时间：
2021-11
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通讯作者：
Tianran Zhou;Cagla Cömert;Xiaoyu Zhou;Lin Lin-Lin;L. Bolund;J. Palmfeldt;Guangdong Tong;Yonglun Luo-Yonglun
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文献类型：
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作者：
Tianran Zhou;Cagla Cömert;Xiaoyu Zhou;Lin Lin-Lin;L. Bolund;J. Palmfeldt;Guangdong Tong;Yonglun Luo-Yonglun
线粒体功能障碍在代谢相关性脂肪肝（MAFLD）中起着关键作用。本研究旨在表征由游离脂肪酸（FFA）（棕榈酸酯和油酸酯）过载24小时触发的人MAFLD Huh7细胞模型中的线粒体功能障碍。我们研究了它对细胞能量代谢的影响，并确定了MAFLD治疗的潜在靶点。FFA处理的细胞表现出脂滴的积累和活力略有下降，但线粒体超氧化物水平没有显着变化。生物能量分析表明，转向更多的呼吸和糖酵解发酵。综合转录组学和蛋白质组学分析确定了显著参与脂肪酸处理和代谢的基因表达的变化。在蛋白质组学和转录组学中，7个基因的表达一致且显著（p < 0.05）改变（4个上调和3个下调基因）。FFA处理的Huh7细胞模型是研究脂肪酸代谢的合适体外模型，并且适合于研究线粒体、糖酵解和多种代谢途径在MAFLD中的作用。我们的综合分析为使用该模型进行药物发现和筛选奠定了基础。
Mitochondrial dysfunction plays a critical role in metabolic associated fatty liver disease (MAFLD). This study aims to characterize mitochondrial dysfunctions in a human MAFLD Huh7 cell model triggered by free fatty acid (FFA) (palmitate and oleate) overload for 24 hours. We investigate its impact on cellular energy metabolism and identify potential targets for MAFLD treatment. FFA-treated cells displayed an accumulation of lipid droplets and slightly decreased viability but no significant changes in mitochondrial superoxide levels. Bioenergetic analysis showed a shift to more respiration and less glycolytic fermentation. Comprehensive transcriptomics and proteomics analyses identified changes in the expression of genes prominently involved in fatty acid handling and metabolism. The expressions of seven genes were consistently and significantly (p < 0.05) altered (4 upregulated and 3 downregulated genes) in both proteomics and transcriptomics. The FFA-treated Huh7 cell model is an appropriate in vitro model to study fatty acid metabolism and suitable to investigate the role of mitochondria, glycolysis, and multiple metabolic pathways in MAFLD. Our comprehensive analyses form a basis for drug discovery and screening using this model.