多组分综合分析结合控制理论和基因组级代谢模型的计算模拟揭示了在棕榈酸诱导的脂毒性下控制人类星形胶质细胞的生物转换

Andrea Angarita-Rodríguez, Nicolás Mendoza-Mejía, Janneth González, A. Aristizabal, Oscar Hidalgo-lanussa, Juan J. Rubio-Mesa, G. Barreto, A. Pinzón
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引用次数: 1

摘要

星形胶质细胞在大脑的各种过程中发挥重要作用,包括神经退行性疾病等病理条件。最近的研究表明,棕榈酸(PA)等饱和脂肪酸的增加会引发大脑中的促炎途径。合成神经类固醇(如替博龙)的使用已证明具有神经保护机制。然而,对于PA的神经退行性作用和替博龙的神经保护机制缺乏系统的广泛研究。在这项研究中,我们将多组学数据(转录组和蛋白质组)整合到人类星形胶质细胞基因组尺度代谢模型中,以研究棕榈酸盐治疗期间星形胶质细胞的反应。我们评估了三种情况下的代谢通量(健康、PA诱导炎症和PA炎症下的替博龙治疗)。我们还应用了控制论方法来确定那些在星形细胞系统中施加更多控制的反应。我们的研究结果表明,PA通过抑制叶酸循环和脂肪酸β-氧化以及上调酮体形成来调节中枢和次级代谢,显示出能量来源使用的开关。我们发现pa介导的细胞调节下有25个代谢开关,其中9个仅在炎症情况下起关键作用,而在替博龙保护情况下不起作用。在这些反应中,抑制性、总偶联和定向偶联是关键发现,在代谢途径的(去)调节中起着基本作用,这些代谢途径可能增加神经毒性并代表潜在的治疗靶点。最后,我们方法的总体框架有助于理解复杂的代谢调节,并可用于星形胶质细胞调节机制的硅探索,指导未来更复杂的神经退行性疾病的实验工作。
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Multi-Omics Integrative Analysis Coupled to Control Theory and Computational Simulation of a Genome-Scale metabolic Model Reveal Controlling Biological Switches in Human Astrocytes Under Palmitic Acid-Induced Lipotoxicity
Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatory pathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, broad studies, with a systemic point of view on the neurodegenerative role of PA and the neuro-protective mechanisms of tibolone are lacking. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also applied a control theory approach to identify those reactions that exert more control in the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a switch in energy source use through inhibition of folate cycle and fatty acid β-oxidation and upregulation of ketone bodies formation. We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation in metabolic pathways that may increase neurotoxicity and represent potential treatment targets. Finally, the overall framework of our approach facilitates the understanding of complex metabolic regulation, and it can be used for in silico exploration of the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases.
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