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

Elife. 2021 May 27;10:e67452. doi: 10.7554/eLife.67452.

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.

Keywords: SIRT1; c-Myc; cell biology; embryogenesis; embryonic stem cells; mouse; neural development; regenerative medicine; sphingomyelin degradation; stem cells.

Plain Language Summary

All cells in the brain start life as stem cells which are yet to have a defined role in the body. A wide range of molecules and chemical signals guide stem cells towards a neuronal fate, including a group of molecules called sphingolipids. These molecules sit in the membrane surrounding the cell and play a pivotal role in a number of processes which help keep the neuronal cell healthy. Various enzymes work together to break down sphingolipids and remove them from the membrane. Defects in these enzymes can result in excess levels of sphingolipids, which can lead to neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease. But how these enzymes are used and controlled during neuronal development is still somewhat of a mystery. To help answer this question, Fan et al. studied an enzyme called SIRT1 which has been shown to alleviate symptoms in animal models of neurodegenerative diseases. Stem cells were extracted from a mouse embryo lacking the gene for SIRT1 and cultured in the laboratory. These faulty cells were found to have superfluous amounts of sphingolipids, which made their membranes more fluid and reduced their ability to develop into neuronal cells. Further investigation revealed that SIRT1 regulates the degradation of sphingolipids by promoting the production of another enzyme called SMPDL3B. Fan et al. also found that when female mice were fed a high-fat diet, this caused sphingolipids to accumulate in their embryos which lacked the gene for SIRT1; this, in turn, impaired the neural development of their offspring. These findings suggest that targeting SIRT1 may offer new strategies for treating neurological diseases. The discovery that embryos deficient in SIRT1 are sensitive to high-fat diets implies that activating this enzyme might attenuate some of the neonatal complications associated with maternal obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Gene Expression Regulation, Developmental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / enzymology*
  • Neural Stem Cells / enzymology*
  • Neurogenesis*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Sphingolipids / metabolism*
  • Transcription, Genetic

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Sphingolipids
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • sphingomyelinase-like phosphodiesterase 3b, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1

Associated data

  • GEO/GSE163920