Targeting a ceramide double bond improves insulin resistance and hepatic steatosis

Bhagirath Chaurasia, Trevor S. Tippetts, Rafael Mayoral Monibas, Jinqi Liu, Ying Li, Liping Wang, Joseph L. Wilkerson, C. Rufus Sweeney, Renato Felipe Pereira, Doris Hissako Sumida, J. Alan Maschek, James E. Cox, Vincent Kaddai, Graeme Iain Lancaster, Monowarul Mobin Siddique, Annelise Poss, Mackenzie Pearson, Santhosh Satapati, Heather Zhou, David G. McLarenStephen F. Previs, Ying Chen, Ying Qian, Aleksandr Petrov, Margaret Wu, Xiaolan Shen, Jun Yao, Christian N. Nunes, Andrew D. Howard, Liangsu Wang, Mark D. Erion, Jared Rutter, William L Holland, David E. Kelley, Scott A. Summers

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16 Scopus citations

Abstract

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase-1 (DES1) which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals, or tissue-specific deletion in the liver, and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed new ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.

Original languageEnglish (US)
JournalScience
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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ASJC Scopus subject areas

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Chaurasia, B., Tippetts, T. S., Monibas, R. M., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., ... Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science. https://doi.org/10.1126/science.aav3722