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

Abstract

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.

• 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-Peiffer, Gregory J Cooney, Magdalene K Montgomery, Jonathan C Morris, Anthony S Don
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 3165 (08 21 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30131496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Fatty Acids
• Sphingolipids
• Oxidoreductases
• dihydroceramide desaturase

Topics

• Animals
• Cell Respiration (drug effects)
• Diet, High-Fat
• Enzyme Inhibitors (chemistry, pharmacology)
• Fatty Acids (metabolism)
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism)
• Muscle, Skeletal (metabolism)
• Oxidation-Reduction
• Oxidoreductases (antagonists & inhibitors, metabolism)
• Sphingolipids (metabolism)