SIRT1-regulated sphingolipid metabolism is important for neural differentiation of mouse embryonic stem cells Wei Fan,1 Shuang Tang, 1, 6 Xiaojuan Fan, 2 Xiaojiang Xu, 3 Leping Li, 4 Jian Xu, 5 Jian-Liang Li, 3 Zefeng Wang, 2 and Xiaoling Li 1, * 1Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA 2CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China 3Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA 4Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA 5Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 6Current address: Cancer Institute and Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China 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 a number of 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 sphingomyelins 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, and further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.
National Institute of Environmental Health Sciences
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