Osorio Daniel, Pinzón Andrés, Martín-Jiménez Cynthia, Barreto George E, González Janneth
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, United States.
Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogotá, Colombia.
Front Neurosci. 2020 Jan 31;13:1410. doi: 10.3389/fnins.2019.01410. eCollection 2019.
Inflammation is a complex biological response to injuries, metabolic disorders or infections. In the brain, astrocytes play an important role in the inflammatory processes during neurodegenerative diseases. Recent studies have shown that the increase of free saturated fatty acids such as palmitic acid produces a metabolic inflammatory response in astrocytes generally associated with damaging mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagic defects. In this aspect, the synthetic neurosteroid tibolone has shown to exert protective functions against inflammation in neuronal experimental models without the tumorigenic effects exerted by sexual hormones such as estradiol and progesterone. However, there is little information regarding the specific mechanisms of tibolone in astrocytes during inflammatory insults. In the present study, we performed a genome-scale metabolic reconstruction of astrocytes that was used to study astrocytic response during an inflammatory insult by palmitate through Flux Balance Analysis methods and data mining. In this aspect, we assessed the metabolic fluxes of human astrocytes under three different scenarios: healthy (normal conditions), induced inflammation by palmitate, and tibolone treatment under palmitate inflammation. Our results suggest that tibolone reduces the L-glutamate-mediated neurotoxicity in astrocytes through the modulation of several metabolic pathways involved in glutamate uptake. We also identified a set of reactions associated with the protective effects of tibolone, including the upregulation of taurine metabolism, gluconeogenesis, cPPAR and the modulation of calcium signaling pathways. In conclusion, the different scenarios studied in our model allowed us to identify several metabolic fluxes perturbed under an inflammatory response and the protective mechanisms exerted by tibolone.
炎症是机体对损伤、代谢紊乱或感染的一种复杂生物学反应。在大脑中，星形胶质细胞在神经退行性疾病的炎症过程中发挥着重要作用。最近的研究表明，游离饱和脂肪酸（如棕榈酸）的增加会在星形胶质细胞中引发代谢性炎症反应，这通常与氧化应激、内质网应激和自噬缺陷等损伤机制相关。在这方面，合成神经甾体替勃龙已被证明在神经元实验模型中对炎症具有保护作用，且不会产生雌二醇和孕酮等性激素所具有的致瘤效应。然而，关于替勃龙在炎症损伤期间对星形胶质细胞发挥作用的具体机制，目前所知甚少。在本研究中，我们对星形胶质细胞进行了全基因组规模的代谢重建，通过通量平衡分析方法和数据挖掘来研究棕榈酸引发炎症损伤时星形胶质细胞的反应。在此方面，我们评估了人类星形胶质细胞在三种不同情况下的代谢通量：健康状态（正常条件）、棕榈酸诱导炎症以及在棕榈酸炎症状态下进行替勃龙处理。我们的结果表明，替勃龙通过调节参与谷氨酸摄取的多种代谢途径，降低了星形胶质细胞中L - 谷氨酸介导的神经毒性。我们还确定了一组与替勃龙保护作用相关的反应，包括牛磺酸代谢上调、糖异生、cPPAR以及钙信号通路的调节。总之，我们模型中所研究的不同情况使我们能够识别炎症反应中受到干扰的几种代谢通量以及替勃龙发挥的保护机制。
