Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Division of Biomedical Sciences, and Neuroscience Graduate Program, School of Medicine, University of California Riverside, Riverside, CA, USA.
Commun Biol. 2023 Jul 29;6(1):789. doi: 10.1038/s42003-023-05147-9.
Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.
胆固醇是一种重要的膜结构成分和类固醇激素前体，参与许多信号转导过程。星形胶质细胞调节大脑胆固醇稳态，并为神经元提供胆固醇。ATP 结合盒转运蛋白 A1（ABCA1）是星形胶质细胞中主要的胆固醇外排转运蛋白。在这里，我们展示了源自脆性 X 综合征（FXS）男性的诱导多能干细胞（iPSC）产生的星形胶质细胞中胆固醇稳态失调，这是遗传性智力障碍的最常见原因。与对照组相比，FXS 人类和小鼠星形胶质细胞中的 ABCA1 水平降低。胆固醇的积累与 FXS 小鼠星形胶质细胞脂质组中去氢胆固醇和多不饱和磷脂的增加有关。星形胶质细胞对细胞因子暴露的异常反应以及人类 FXS 星形胶质细胞分泌组中抗炎和细胞因子谱的改变表明炎症因子对胆固醇稳态的改变有贡献。我们的结果表明星形胶质细胞脂代谢发生变化，这可能会严重调节膜特性并影响 FXS 星形胶质细胞中的胆固醇转运，为 FXS 的治疗提供了靶点。
