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
AUTHORS (22)
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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