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Turner, Nigel; Lim, Xin Ying; Toop, Hamish D; Osborne, Brenna; Brandon, Amanda E; Taylor, Elysha N; Fiveash, Corrine E; Govindaraju, Hemna; Teo, Jonathan D; McEwen, Holly P; Couttas, Timothy A; Butler, Stephen M; Das, Abhirup; Kowalski, Greg M; Bruce, Clinton R; Hoehn, Kyle L; Fath, Thomas; Schmitz-Peiffer, Carsten; Cooney, Gregory J; Montgomery, Magdalene K; Morris, Jonathan C; Don, Anthony S
Nature communications, 08/2018, Letnik: 9, Številka: 1Journal Article
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.
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