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

Nigel Turner,Xin Ying Lim,Jonathan C Morris,Greg M Kowalski,Kyle L Hoehn,Timothy A Couttas,Magdalene K Montgomery ,Brenna Osborne,Gregory J Cooney,Hamish D Toop,Thomas Fath,Clinton R Bruce,Elysha N Taylor,Holly P Mcewen,Carsten Schmitz‐Peiffer ,Jonathan D Teo,Hemna Govindaraju,Corrine E Fiveash ,Stephen Butler ,Abhirup Das,Amanda E Brandon,Anthony S Don

doi:10.1038/s41467-018-05613-7

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.

Highlights

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology
To develop isoform-selective CerS inhibitors, we started with the multiple sclerosis drug Fingolimod (FTY720, Gilenya), which is an analogue of the endogenous lipid sphingosine[28]
Following its phosphorylation in vivo, Fingolimod is a potent agonist of sphingosine 1-phosphate receptors, the nonphosphorylated pro-drug exhibits non-selective inhibition of ceramide synthases as an off-target effect[29,30]

Summary

Introduction

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Ceramide synthesis in mammals is catalysed by a family of six ceramide synthases (CerS1-6) These enzymes transfer a variable length fatty acyl-coenzyme A (CoA) to the amine group of a sphingoid base[1]. Ceramide synthesis may act as a direct metabolic sensor of fatty acid availability, feeding back to regulate metabolic processes. Another ceramide species implicated in insulin resistance is C18:011,22,23. CerS1 inhibition is shown to promote fatty acid oxidation in SkM and reduce overall adiposity in mice fed a HFD

Methods

Results

Conclusion