SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B.
SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B.
复制标题
SIRT1通过c-Myc-SMPDL3B调节小鼠胚胎干细胞的鞘脂代谢和神经分化
作者：
Fan W;Tang S;Fan X;Fang Y;Xu X;Li L;Xu J;Li JL;Wang Z;Li X
鞘磷脂是细胞膜的重要结构成分，是控制细胞生长、分化和凋亡的重要信号分子。鞘脂在大脑中含量特别丰富，神经鞘脂降解缺陷与几种人类神经退行性疾病有关。然而，调控鞘磷脂代谢的分子机制仍不清楚。在这里，我们报道了在小鼠胚胎干细胞(MESCs)中，鞘磷脂的降解是受SIRT1转录控制的，SIRT1是一种高度保守的哺乳动物NAD+依赖的蛋白质去乙酰基酶。SIRT1的缺失导致神经鞘蛋白在mESCs中的积累，主要是由于SMPDL3B的减少，SMPDL3B是一种与GPI锚定的质膜结合的神经鞘磷脂磷酸二酯酶。从机制上讲，SIRT1通过c-Myc调控Smpd13b的转录。在功能上，SIRT1缺乏导致神经鞘磷脂的积聚增加了细胞膜的流动性，损害了体外和体内的神经分化。我们的发现发现了鞘磷脂动态平衡和神经分化的关键调控机制，进一步暗示对SIRT1介导的鞘磷脂降解的药理学操作可能有利于人类神经疾病的治疗。大脑中的所有细胞都是以干细胞的形式开始生命的，而干细胞在体内还没有明确的作用。一系列分子和化学信号引导干细胞走向神经元的命运，包括一组被称为鞘脂的分子。这些分子位于细胞周围的膜上，在许多有助于保持神经细胞健康的过程中发挥着关键作用。各种酶共同作用，分解鞘脂并将其从膜上移除。这些酶的缺陷会导致鞘脂水平过高，这可能会导致神经退行性疾病，如阿尔茨海默氏症、帕金森氏症和亨廷顿病。但这些酶在神经元发育过程中是如何使用和控制的，在某种程度上仍然是一个谜。为了帮助回答这个问题，Fan等人。研究了一种名为SIRT1的酶，该酶已被证明可以缓解神经退行性疾病动物模型的症状。从缺乏SIRT1基因的小鼠胚胎中提取干细胞，并在实验室进行培养。这些有缺陷的细胞被发现含有过量的鞘磷脂，这使得它们的膜更具流动性，并降低了它们发育成神经细胞的能力。进一步的研究发现，SIRT1通过促进另一种名为SMPDL3B的酶的产生来调节鞘脂的降解。Fan等人还发现，当雌性小鼠喂食高脂肪食物时，这会导致缺乏SIRT1基因的胚胎中神经鞘脂类积累；这反过来又损害了它们后代的神经发育。这些发现表明，靶向SIRT1可能为治疗神经系统疾病提供新的策略。缺乏SIRT1的胚胎对高脂肪饮食敏感这一发现表明，激活这种酶可能会减轻与母亲肥胖有关的一些新生儿并发症。
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. 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.