Department of Medicine, Division of Medical Oncology and Hematology, University of Louisville School of Medicine, Louisville, Kentucky (W.J.R., S.B.H., S.M.S., N.A.H., A.J.O., M.A.D., L.J.S.); Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York (M.H.-C., L.M.O., Y.A.H.); Northport Veteran Affairs Medical Center, Northport, New York (L.M.O., Y.A.H.); School of Nutritional Sciences, College of Agriculture, Life and Environmental Sciences, and University of Arizona Cancer Center, University of Arizona, Tucson, Arizona (C.L.D., C.X., J.M.S., A.J.S.); and Brown Cancer Center, University of Louisville, Louisville, Kentucky (L.J.S.).
Department of Medicine, Division of Medical Oncology and Hematology, University of Louisville School of Medicine, Louisville, Kentucky (W.J.R., S.B.H., S.M.S., N.A.H., A.J.O., M.A.D., L.J.S.); Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York (M.H.-C., L.M.O., Y.A.H.); Northport Veteran Affairs Medical Center, Northport, New York (L.M.O., Y.A.H.); School of Nutritional Sciences, College of Agriculture, Life and Environmental Sciences, and University of Arizona Cancer Center, University of Arizona, Tucson, Arizona (C.L.D., C.X., J.M.S., A.J.S.); and Brown Cancer Center, University of Louisville, Louisville, Kentucky (L.J.S.)
Mol Pharmacol. 2024 Feb 15;105(3):131-143. doi: 10.1124/molpharm.123.000788.
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. SIGNIFICANCE STATEMENT: The current study demonstrates that ceramide synthase (CerS) expression in specific tissues correlates not only with ceramide species but contributes to the generation of complex sphingolipids as well. As many of the CerSs and/or specific ceramide species have been implicated in disease, these studies suggest the potential for CerSs as therapeutic targets and the use of sphingolipid species as diagnostics in specific tissues.
鞘脂是存在于所有真核细胞中的一类重要脂质，它们调节关键的细胞过程。鞘脂代谢失衡与人类的几种疾病有关。神经酰胺是鞘脂代谢的核心物质，主要由 6 种神经酰胺合酶 (CerS) 同工酶 (CerS1-6) 合成，每种同工酶对不同的脂肪酸链长具有偏好性。尽管已知人类 CerS mRNA 表达的组织分布以及 CerS 同工酶在合成不同酰基链长的神经酰胺中的作用，但尚不清楚 CerS 表达如何在组织内决定神经酰胺和下游代谢物。在这项研究中，我们分析了 3 个月龄 C57BL/6J 小鼠脑、心、肾、肝、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，CerS 表达是组织内神经酰胺种类的预测因子。有趣的是，尽管 CerS 表达不能预测所有组织中的复杂鞘脂种类，但在每种组织中测量的 CerS 对总鞘脂的贡献的综合评分与 CerS 表达相关。最后，我们确定了小鼠组织中最丰富的神经酰胺种类与相应人类组织中的 CerS mRNA 表达一致（基于链长偏好），这表明小鼠是神经酰胺和鞘脂研究的相关临床前模型。
本研究表明，特定组织中的 CerS 表达不仅与神经酰胺种类相关，而且还与复杂鞘脂的生成有关。由于许多 CerS 和/或特定的神经酰胺种类与疾病有关，这些研究表明 CerS 作为治疗靶点的潜力以及特定组织中鞘脂种类作为诊断标志物的潜力。
