SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B

• DOI: 10.7554/elife.67452
• Publication Date: 2021-05-27T12:00:40Z
• Authors: Wei Fan; Shuang Tang; Xiaojuan Fan; Yi Fang; Xiaojiang Xu; Leping Li; Jian Xu; Jian-Liang Li; Zefeng Wang; Xiaoling Li
• Keywords: Sphingolipid; Sphingomyelin phosphodiesterase

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling growth, differentiation, apoptosis. particularly abundant in the brain, defects sphingolipid degradation associated with several human neurodegenerative diseases. However, molecular mechanisms governing metabolism remain unclear. Here, we report that is under transcriptional control SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, mouse embryonic stem cells (mESCs). Deletion SIRT1 results accumulation sphingomyelin mESCs, primarily due to reduction SMPDL3B, GPI-anchored plasma membrane bound phosphodiesterase. Mechanistically, regulates transcription Smpdl3b through c-Myc. Functionally, deficiency-induced increases fluidity impairs neural differentiation vitro vivo. Our findings discover key regulatory mechanism for homeostasis further imply pharmacological manipulation SIRT1-mediated might be beneficial treatment neurological diseases.All brain start life as which yet have defined role body. A wide range chemical signals guide towards neuronal fate, including group called sphingolipids. These sit surrounding play pivotal number processes help keep healthy. Various enzymes work together break down sphingolipids remove them from membrane. Defects these can result excess levels sphingolipids, lead diseases, such Alzheimer’s, Parkinson’s Huntington’s disease. But how used controlled during development still somewhat mystery. To answer this question, Fan et al. studied an enzyme has been shown alleviate symptoms animal models Stem were extracted embryo lacking gene cultured laboratory. faulty found superfluous amounts made their more fluid reduced ability develop into cells. Further investigation revealed by promoting production another SMPDL3B. also when female mice fed high-fat diet, caused accumulate embryos lacked SIRT1; this, turn, impaired offspring. suggest targeting may offer new strategies treating The discovery deficient sensitive diets implies activating attenuate some neonatal complications maternal obesity.