Sugimoto Masayuki, Wakabayashi Masato, Shimizu Yoichi, Yoshioka Takeshi, Higashino Kenichi, Numata Yoshito, Okuda Tomohiko, Zhao Songji, Sakai Shota, Igarashi Yasuyuki, Kuge Yuji
Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo, Japan.
PLoS One. 2016 Mar 24;11(3):e0152191. doi: 10.1371/journal.pone.0152191. eCollection 2016.
Obesity was reported to cause kidney injury by excessive accumulation of sphingolipids such as sphingomyelin and ceramide. Sphingomyelin synthase 2 (SMS2) is an important enzyme for hepatic sphingolipid homeostasis and its dysfunction is considered to result in fatty liver disease. The expression of SMS2 is also high in the kidneys. However, the contribution of SMS2 on renal sphingolipid metabolism remains unclear. Imaging mass spectrometry is a powerful tool to visualize the distribution and provide quantitative data on lipids in tissue sections. Thus, in this study, we analyzed the effects of SMS2 deficiency on the distribution and concentration of sphingomyelins in the liver and kidneys of mice fed with a normal-diet or a high-fat-diet using imaging mass spectrometry and liquid chromatography/electrospray ionization-tandem mass spectrometry. Our study revealed that high-fat-diet increased C18-C22 sphingomyelins, but decreased C24-sphingomyelins, in the liver and kidneys of wild-type mice. By contrast, SMS2 deficiency decreased C18-C24 sphingomyelins in the liver. Although a similar trend was observed in the whole-kidneys, the effects were minor. Interestingly, imaging mass spectrometry revealed that sphingomyelin localization was specific to each acyl-chain length in the kidneys. Further, SMS2 deficiency mainly decreased C22-sphingomyelin in the renal medulla and C24-sphingomyelins in the renal cortex. Thus, imaging mass spectrometry can provide visual assessment of the contribution of SMS2 on acyl-chain- and region-specific sphingomyelin metabolism in the kidneys.
据报道，肥胖会因鞘磷脂（如鞘磷脂和神经酰胺）的过度积累而导致肾损伤。鞘磷脂合酶2（SMS2）是肝脏鞘脂稳态的一种重要酶，其功能障碍被认为会导致脂肪肝疾病。SMS2在肾脏中的表达也很高。然而，SMS2对肾鞘脂代谢的作用仍不清楚。成像质谱是一种强大的工具，可用于可视化组织切片中脂质的分布并提供定量数据。因此，在本研究中，我们使用成像质谱和液相色谱/电喷雾电离串联质谱分析了SMS2缺乏对正常饮食或高脂饮食喂养的小鼠肝脏和肾脏中鞘磷脂分布和浓度的影响。我们的研究表明，高脂饮食会增加野生型小鼠肝脏和肾脏中C18 - C22鞘磷脂的含量，但会降低C24 - 鞘磷脂的含量。相比之下，SMS2缺乏会降低肝脏中C18 - C24鞘磷脂的含量。虽然在整个肾脏中观察到了类似的趋势，但影响较小。有趣的是，成像质谱显示鞘磷脂的定位在肾脏中对每个酰基链长度具有特异性。此外，SMS2缺乏主要降低肾髓质中的C22 - 鞘磷脂和肾皮质中的C24 - 鞘磷脂。因此，成像质谱可以直观评估SMS2对肾脏中酰基链特异性和区域特异性鞘磷脂代谢的作用。
