Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.

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.

• Authors: 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 McLaren, Stephen 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
• Journal: Science (New York, N.Y.) (Science) Vol. 365 Issue 6451 Pg. 386-392 (07 26 2019) ISSN: 1095-9203 [Electronic] United States
• PMID: 31273070 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019, American Association for the Advancement of Science.

Chemical References

• Ceramides
• Leptin
• Membrane Proteins
• Sphingolipids
• dihydroceramide
• Oxidoreductases
• Degs protein, mouse

Topics

• Animals
• Ceramides (chemistry, genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Fatty Liver (genetics, metabolism)
• Gene Deletion
• Insulin Resistance (genetics)
• Leptin (deficiency)
• Membrane Proteins (genetics)
• Mice
• Mice, Mutant Strains
• Oxidoreductases (genetics)
• Sphingolipids (chemistry, metabolism)