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

Research output: Contribution to journalArticle

34 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 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)
Pages (from-to)386-392
Number of pages7
JournalScience
Volume365
Issue number6451
DOIs
StatePublished - Jul 26 2019

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    Chaurasia, B., Tippetts, T. S., Monibas, R. M., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Rufus Sweeney, C., Pereira, R. F., Sumida, D. H., Alan Maschek, J., 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, 365(6451), 386-392. https://doi.org/10.1126/science.aav3722