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

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
DOI: 10.1038/s41467-018-05613-7 Publication Date: 2018-08-03T08:33:43Z
ABSTRACT
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.
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