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https://hdl.handle.net/2440/129635
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Type: | Journal article |
Title: | A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism |
Author: | Turner, N. Lim, X.Y. Toop, H.D. Osborne, B. Brandon, A.E. Taylor, E.N. Fiveash, C.E. Govindaraju, H. Teo, J.D. McEwen, H.P. Couttas, T.A. Butler, S.M. Das, A. Kowalski, G.M. Bruce, C.R. Hoehn, K.L. Fath, T. Schmitz-Peiffer, C. Cooney, G.J. Montgomery, M.K. et al. |
Citation: | Nature Communications, 2018; 9(1):3165-1-3165-14 |
Publisher: | Nature Publishing Group |
Issue Date: | 2018 |
ISSN: | 2041-1723 2041-1723 |
Statement of Responsibility: | Nigel Turner, Xin Ying Lim, Hamish D. Toop, Brenna Osborne, Amanda E. Brandon, Elysha N. Taylor ... et al. |
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. |
Keywords: | Muscle, Skeletal |
Rights: | © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. |
DOI: | 10.1038/s41467-018-05613-7 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1126135 |
Published version: | http://dx.doi.org/10.1038/s41467-018-05613-7 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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