Division of Biological Science and Technology, College of Science and Technology, Yonsei University, 1 Yonseidae-gil, Wonju, 220-710, Republic of Korea.
Mol Biol Rep. 2012 Apr;39(4):4215-21. doi: 10.1007/s11033-011-1207-2. Epub 2011 Jul 20.
Most living organisms exhibit circadian rhythms in physiology and behavior. These oscillations are generated by an endogenous circadian clock and control many biological processes. Ceramide has attracted attention as a signal mediator in diverse cell processes including cell death and differentiation. The relationships between ceramide expression levels and the circadian clock have not previously been investigated. To determine if there are circadian variations in the content of ceramide, we measured ceramide concentrations in the livers of wild-type (WT) and mPer1/mPer2 double knockout (DKO) mice. The ceramide concentration in WT mice was dramatically increased at Zeitgeber Time 9 (ZT9; 9 h after lights-on time) and ZT21 but no rhythmicity in ceramide expression was seen in DKO mice. Because ceramide can be generated by the hydrolysis of sphingomyelin via sphingomyelinase (SMase), or by ceramide synthase (CerS)-mediated synthesis, we assayed the expression patterns of ceramide-related genes using real-time PCR. CerS2 expression levels showed a biphasic pattern of expression in WT mice but no rhythmicity in DKO mice. While the neutral SMase (nSMase) and acidic SMase (aSMase) mRNA in WT mice were expressed in a circadian manner, the correlation between the expression levels of these SMases with times of day was weak in DKO mice. Collectively, our findings suggest that both SMases and CerS2 mRNA expression are regulated by the presence of mPer1/mPer2 circadian clock genes in vivo, and imply that ceramide may play a vital role in circadian rhythms and physiology.
大多数生物体的生理和行为都表现出昼夜节律。这些波动是由内源性生物钟产生的，并控制着许多生物过程。神经酰胺作为一种信号介质，在包括细胞死亡和分化在内的多种细胞过程中引起了关注。神经酰胺表达水平与生物钟之间的关系尚未被研究过。为了确定神经酰胺的含量是否存在昼夜变化，我们测量了野生型（WT）和 mPer1/mPer2 双敲除（DKO）小鼠肝脏中的神经酰胺浓度。WT 小鼠的神经酰胺浓度在 Zeitgeber Time 9（ZT9；光照后 9 小时）和 ZT21 时急剧增加，但 DKO 小鼠中没有观察到神经酰胺表达的节律性。因为神经酰胺可以通过神经鞘氨醇酶（SMase）水解鞘磷脂产生，也可以通过神经酰胺合酶（CerS）介导的合成产生，所以我们使用实时 PCR 测定了与神经酰胺相关的基因的表达模式。WT 小鼠中的 CerS2 表达水平呈双峰模式，但 DKO 小鼠中没有节律性。虽然 WT 小鼠中的中性 SMase（nSMase）和酸性 SMase（aSMase）mRNA 呈昼夜节律表达，但这些 SMases 的表达水平与 DKO 小鼠的时间相关性较弱。总之，我们的发现表明，SMase 和 CerS2 mRNA 表达均受体内 mPer1/mPer2 生物钟基因的调节，并暗示神经酰胺可能在昼夜节律和生理学中发挥重要作用。
