Cholesterol sulfate alters astrocyte metabolism and provides protection against oxidative stress
Cholesterol sulfate alters astrocyte metabolism and provides protection against oxidative stress
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DOI：
10.1016/j.brainres.2019.146378
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发表时间：
2019-11-15
期刊：
影响因子：
2.9
通讯作者：
Yang, Shao-Hua
中科院分区：
文献类型：
--
作者：
Prah, Jude;Winters, Ali;Yang, Shao-Hua
硫酸胆固醇 (CS) 是人体血浆中最重要的已知甾醇硫酸盐之一，并且作为多种人体组织中的正常成分存在。在大脑和外周中，CS 是合成磺化肾上腺类固醇（如孕烯醇酮硫酸盐和脱氢表雄酮 (DHEA) 硫酸盐）的底物，也是许多生物膜（包括红细胞）的成分，在红细胞中发挥稳定剂的作用。它还充当胆固醇合成的内源性调节剂。然而，CS在脑代谢和神经系统疾病中的作用尚不清楚。在当前的研究中，我们研究了 CS 的神经保护作用及其在脑能量代谢中的作用。使用 Calcein AM 和 MTT 细胞活力测定、流式细胞术、Seahorse 细胞外通量分析和代谢测定试剂盒，在从出生后 0-2 天的 C57BL/6 幼崽皮层和海马 HT-22 细胞系制备的原代星形胶质细胞中测定 CS 的神经保护作用及其对细胞代谢的作用。我们发现CS可减弱谷氨酸和鱼藤酮诱导的HT-22细胞死亡，减少谷氨酸诱导的线粒体膜电位崩溃和活性氧的产生。此外，CS 还激活 Akt/Bcl(2) 通路。我们观察到 CS 通过增加线粒体磷酸化、ATP 和糖原含量来影响星形胶质细胞代谢。我们的研究表明，CS 调节大脑能量代谢，其神经保护作用可能是由于 Akt 信号传导的激活或其减少活性氧产生的能力。
Cholesterol sulfate (CS) is one of the most important known sterol sulfates in human plasma and it is present as a normal constituent in a variety of human tissues. In both the brain and periphery, CS serves as a substrate for the synthesis of sulfonated adrenal steroids such as pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate and as a constituent of many biological membranes including red blood cells where it functions as a stabilizing agent. It also acts as an endogenous regulator of cholesterol synthesis. However, the role of CS in brain metabolism and neurological disorder is unclear. In the current study we investigated the neuroprotective action of CS as well as its role in brain energy metabolism. The neuroprotective effect of CS and its role on cell metabolism were determined in primary astrocyte prepared from the cortex of postnatal day 0-2 C57BL/6 pups and a hippocampal HT-22 cell line using Calcein AM and MTT cell viability assay, flow cytometry, Seahorse extracellular flux analysis, and metabolism assay kits. We found that CS attenuates glutamate and rotenone induced cell death in HT-22 cells, decrease glutamate induced mitochondria membrane potential collapse, and reactive oxygen species production. Additionally, CS activates the Akt/Bcl(2) pathway. We observed that CS impacts astrocyte metabolism by increasing mitochondrial phosphorylation, ATP, and glycogen contents. Our study demonstrated that CS modulates brain energy metabolism and its neuroprotective effects might be due to the activation of Akt signaling or its ability to decrease reactive oxygen species production.