Taniguchi Makoto, Okazaki Toshiro
Department of Life Science, Medical Research Institute, Kanazawa Medical University, Kahoku, Japan.
Research Institute for Bioresources and Biotechnology, Kanazawa Prefectural University, Nonoichi, Japan.
J Lipid Atheroscler. 2020 Sep;9(3):380-405. doi: 10.12997/jla.2020.9.3.380. Epub 2020 Jul 29.
Ceramide and sphingomyelin (SM) are major components of the double membrane-bound sphingolipids. Ceramide is an essential bioactive lipid involved in numerous cell processes including apoptosis, necrosis, and autophagy-dependent cell death. Inversely, SM regulates opposite cellular processes such as proliferation and migration by changing receptor-mediated signal transduction in the lipid microdomain. SM is generated through a transfer of phosphocholine from phosphatidylcholine to ceramide by SM synthases (SMSs). Research during the past several decades has revealed that the ceramide/SM balance in cellular membranes regulated by SMSs is important to decide the cell fate, survival, and proliferation. In addition, recent experimental studies utilizing SMS knockout mice and murine disease models provide evidence that SMS-regulated ceramide/SM balance is involved in human diseases. Here, we review the basic structural and functional characteristics of SMSs and focus on their cellular functions through the regulation of ceramide/SM balance in membrane microdomains. In addition, we present the pathological or physiological implications of SMSs by analyzing their role in SMS-knockout mice and human disease models. This review finally presents evidence indicating that the regulation of ceramide/SM balance through SMS could be a therapeutic target for human disorders.
神经酰胺和鞘磷脂（SM）是双膜结合鞘脂的主要成分。神经酰胺是一种重要的生物活性脂质，参与众多细胞过程，包括细胞凋亡、坏死和自噬依赖性细胞死亡。相反，SM通过改变脂质微区中受体介导的信号转导来调节相反的细胞过程，如增殖和迁移。SM是由鞘磷脂合成酶（SMSs）将磷脂酰胆碱中的磷酸胆碱转移到神经酰胺上生成的。过去几十年的研究表明，由SMSs调节的细胞膜中神经酰胺/SM平衡对于决定细胞命运、存活和增殖至关重要。此外，最近利用SMS基因敲除小鼠和小鼠疾病模型进行的实验研究提供了证据，表明SMS调节的神经酰胺/SM平衡与人类疾病有关。在这里，我们综述了SMSs的基本结构和功能特征，并通过调节膜微区中的神经酰胺/SM平衡来关注它们的细胞功能。此外，我们通过分析它们在SMS基因敲除小鼠和人类疾病模型中的作用，阐述了SMSs的病理或生理意义。本综述最终提供了证据，表明通过SMS调节神经酰胺/SM平衡可能是治疗人类疾病的一个靶点。
