SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B
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Curated by eLife
Evaluation Summary:
This paper will be of broad interest to cell biologists and advances the current understanding of the connection between lipid metabolism and stem cell function. The data generated from multiple complementary experimental approaches are of high quality and convincingly support the claims made.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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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Reviewer #2 (Public Review):
Sphingolipids are key components of cellular membranes and act as signaling molecules in multiple physiologically relevant processes. In their manuscript, Fan et al. discover a role for SIRT1 in regulation of sphingolipid metabolism in embryonic stem cells and investigate its implication in neural differentiation. Based on metabolomics analysis and subsequent confirmatory experiments, the authors observed elevated levels of sphingomyelin in samples from SIRT1-deficient mouse ES cells in comparison to wildtype cells, suggesting a regulatory function for this enzyme in sphingolipid metabolic processes. Mechanistically, the authors describe that SIRT1 controls c-myc-dependent expression of SMPDL3B, a sphingomyelin-degrading phosphodiesterase, which regulates sphingomyelin content in ES cells. In vitro and in …
Reviewer #2 (Public Review):
Sphingolipids are key components of cellular membranes and act as signaling molecules in multiple physiologically relevant processes. In their manuscript, Fan et al. discover a role for SIRT1 in regulation of sphingolipid metabolism in embryonic stem cells and investigate its implication in neural differentiation. Based on metabolomics analysis and subsequent confirmatory experiments, the authors observed elevated levels of sphingomyelin in samples from SIRT1-deficient mouse ES cells in comparison to wildtype cells, suggesting a regulatory function for this enzyme in sphingolipid metabolic processes. Mechanistically, the authors describe that SIRT1 controls c-myc-dependent expression of SMPDL3B, a sphingomyelin-degrading phosphodiesterase, which regulates sphingomyelin content in ES cells. In vitro and in vivo models of neural development further corroborated a lipid metabolism-related role of SIRT1 and SMPDL3B in ES cell biology.
This work describes an intriguing connection between sphingolipid homeostasis and ES cell function/differentiation that provides insight on how lipid metabolism is intertwined with cellular physiology. Following their initial metabolomics-based finding of altered lipid composition in SIRT1 KO ES cells, the authors employ an impressive array of complementary experimental approaches to pinpoint the molecular mechanism and consequences behind this observation. In general, these experiments appeared technically well conducted and conclusive, but still leave some important questions open.
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Reviewer #1 (Public Review):
This paper shows that the sphingomyelin-degrading enzyme SMPDL3B is under transcriptional control of SIRT1 and c-Myc in ESCs, and that loss of SIRT1 lowers sphingomyelin content of ESCs. Sphingomyelin accumulation in SIRT1-deficient ESCs is associated with changes to membrane fluidity and the abundance of several differentiation markers. The paper also includes interesting data showing that maternal HFD feeding increases the SM content of SIRT1 KO embryos. The studies presented are thorough and the data are interesting.
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Evaluation Summary:
This paper will be of broad interest to cell biologists and advances the current understanding of the connection between lipid metabolism and stem cell function. The data generated from multiple complementary experimental approaches are of high quality and convincingly support the claims made.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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