A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

• DOI: 10.1038/s41467-018-05613-7
• Publication Date: 2018-08-03T08:33:43Z
• Authors: Nigel Turner; Xin Ying Lim; Hamish D. Toop; Brenna Osborne; Amanda E. Brandon; Elysha N. Taylor; Corrine E. Fiveash; Hemna Govindaraju; Jonathan D. Teo; Holly P. McEwen; Timothy A. Couttas; Stephen M. Butler; Abhirup Das; Greg M. Kowalski; Clinton R. Bruce; Kyle L. Hoehn; Thomas Fath; Carsten Schmitz-P...; Gregory J. Cooney; Magdalene K. Mont...; Jonathan C. Morris; Anthony S. Don
• Keywords: Ceramide synthase; Sphingolipid

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