TY - JOUR TI - SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B AU - Fan, Wei AU - Tang, Shuang AU - Fan, Xiaojuan AU - Fang, Yi AU - Xu, Xiaojiang AU - Li, Leping AU - Xu, Jian AU - Li, Jian-Liang AU - Wang, Zefeng AU - Li, Xiaoling A2 - Tontonoz, Peter A2 - Kaeberlein, Matt VL - 10 PY - 2021 DA - 2021/05/27 SP - e67452 C1 - eLife 2021;10:e67452 DO - 10.7554/eLife.67452 UR - https://doi.org/10.7554/eLife.67452 AB - Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases. KW - SIRT1 KW - sphingomyelin degradation KW - embryonic stem cells KW - neural development KW - embryogenesis KW - c-Myc JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -