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

0301 basic medicine Transcription, Genetic QH301-705.5 Science Neurogenesis sphingomyelin degradation neural development Cell Line Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences SIRT1 Neural Stem Cells Sirtuin 1 Animals Biology (General) Mice, Knockout Sphingolipids 0303 health sciences Q R Gene Expression Regulation, Developmental Mouse Embryonic Stem Cells Cell Biology embryonic stem cells Cyclic Nucleotide Phosphodiesterases, Type 3 3. Good health Mice, Inbred C57BL c-Myc Medicine embryogenesis Signal Transduction
DOI: 10.7554/elife.67452 Publication Date: 2021-05-27T12:00:40Z
ABSTRACT
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.
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