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: Male; 0301 basic medicine; Science; Cell Respiration; 610; 3101 Biochemistry and Cell Biology; Cardiovascular; Inbred C57BL; Diet, High-Fat; Article; Mice; Inhibitory Concentration 50; 03 medical and health sciences; Animals; Humans; Obesity; anzsrc-for: 31 Biological Sciences; Enzyme Inhibitors; Muscle, Skeletal; Metabolic and endocrine; Nutrition; Sphingolipids; 0303 health sciences; Liver Disease; Diabetes; anzsrc-for: 3101 Biochemistry and Cell Biology; Q; Fatty Acids; Skeletal; Lipid Metabolism; Diet; Mitochondria; 3. Good health; Mice, Inbred C57BL; High-Fat; HEK293 Cells; Liver; 5.1 Pharmaceuticals; Muscle; Insulin Resistance; Digestive Diseases; Oxidoreductases; Oxidation-Reduction; 31 Biological Sciences

AbstractSpecific 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.