Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase (CerS) isoforms (CerS1–6), each with a preference for different fatty acyl chain lengths. Although the tissue distribution of CerS mRNA expression in humans and the roles of CerS isoforms in synthesizing ceramides with different acyl chain lengths are known, it is unknown how CerS expression dictates ceramides and downstream metabolites within tissues. In this study, we analyzed sphingolipid levels and CerS mRNA expression in 3-month-old C57BL/6J mouse brain, heart, kidney, liver, lung, and skeletal muscle. The results showed that CerS expression and sphingolipid species abundance varied by tissue and that CerS expression was a predictor of ceramide species within tissues. Interestingly, although CerS expression was not predictive of complex sphingolipid species within all tissues, composite scores for CerSs contributions to total sphingolipids measured in each tissue correlated to CerS expression. Lastly, we determined that the most abundant ceramide species in mouse tissues aligned with CerS mRNA expression in corresponding human tissues (based on chain length preference), suggesting that mice are relevant preclinical models for ceramide and sphingolipid research.

中文翻译：

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小鼠中神经酰胺合成酶的表达及其在调节酰基链鞘脂中的作用：基线水平的框架以及对衰老和疾病的未来影响

鞘脂是一类重要的脂质，存在于所有真核细胞中，调节关键的细胞过程。鞘脂稳态的紊乱与人类的多种疾病有关。神经酰胺是鞘脂代谢的核心，主要由六种神经酰胺合酶 (CerS) 异构体 (CerS1-6) 合成，每种异构体偏好不同的脂肪酰链长度。尽管人类中 CerS mRNA 表达的组织分布以及 CerS 亚型在合成具有不同酰基链长度的神经酰胺中的作用是已知的，但尚不清楚 CerS 表达如何决定组织内的神经酰胺和下游代谢物。在这项研究中，我们分析了 3 个月大的 C57BL/6J 小鼠大脑、心脏、肾脏、肝脏、肺和骨骼肌中的鞘脂水平和 CerS mRNA 表达。结果表明，CerS 表达和鞘脂种类丰度因组织而异，并且 CerS 表达是组织内神经酰胺种类的预测因子。有趣的是，虽然 CerS 表达并不能预测所有组织内的复杂鞘脂种类，但在每个组织中测量的 CerSs 对总鞘脂贡献的综合得分与 CerS 表达相关。最后，我们确定小鼠组织中最丰富的神经酰胺种类与相应人体组织中的 CerS mRNA 表达一致（基于链长度偏好），这表明小鼠是神经酰胺和鞘脂研究的相关临床前模型。