论文标题：A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

期刊：Nature Communications

作者：Nigel Turner et al

发表时间：2018/08/21

数字识别码：10.1038/s41467-018-05613-7

原文链接：https://www.nature.com/articles/s41467-018-05613-7?utm_source=Other_website&utm_medium=Website_links&utm_content=RenLi-MixedBrand-OAB-Multidisciplinary-China&utm_campaign=OAB_USG_JRCN_RL_article_promotion_sciencenet_Aug_5th

微信链接：https://mp.weixin.qq.com/s/-aDipxpgpJhN_ORFYdeOTw

《自然-通讯》近日发表的一项研究A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism证实，一种神经酰胺合成酶1（CerS1）抑制剂可以有效防止小鼠体内的脂质堆积。肌肉组织内含有大量C18神经酰胺，而名为P053的化合物可以专门抑制高脂饮食小鼠体内的C18神经酰胺合成，减少小鼠体内的脂肪含量。

图源：Pixabay

神经酰胺合成酶参与生理代谢的调节，但研究人员对不同神经酰胺的作用并不完全清楚。据预测，抑制某些神经酰胺合成酶会对代谢健康产生巨大益处，而抑制另一些则会产生不利影响。不过，研究人员尚未研发出一种能作用于生物体内，且具有高活性和选择性等特性的抑制剂。

澳大利亚新南威尔士大学的Nigel Turner和同事合成了一种名为P053的分子，他们发现这种CerS1抑制剂可以减少高脂饮食小鼠体内储存的脂肪，同时不会导致胰岛素抵抗产生变化。作者认为，可能是小鼠肌肉内脂肪酸氧化的增强导致了脂质堆积的减少。

图2：P053选择性地降低培养的细胞中的C18鞘脂类。Turner et al.

作者合成了能抑制CerS1的小分子，并证实这种酶在肌肉脂肪酸氧化和体内脂肪储存的内源性调控中起到了关键作用。这项研究结果或为治疗肥胖开辟了一条全新的潜在路径，但结果能否适用于人类仍待进一步研究。

摘要：Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.

阅读论文全文请访问：https://www.nature.com/articles/s41467-018-05613-7?utm_source=Other_website&utm_medium=Website_links&utm_content=RenLi-MixedBrand-OAB-Multidisciplinary-China&utm_campaign=OAB_USG_JRCN_RL_article_promotion_sciencenet_Aug_5th

（来源：科学网）