Targeting a ceramide double bond improves insulin resistance and hepatic steatosis

• Published in: Science (American Association for the Advancement of Science) Vol. 365; no. 6451; pp. 386 - 392
• Main Authors: Chaurasia, Bhagirath, Tippetts, Trevor S., Monibas, Rafael Mayoral, Liu, Jinqi, Li, Ying, Wang, Liping, Wilkerson, Joseph L., Sweeney, C. Rufus, Pereira, Renato Felipe, Sumida, Doris Hissako, Maschek, J. Alan, Cox, James E., Kaddai, Vincent, Lancaster, Graeme Iain, Siddique, Monowarul Mobin, Poss, Annelise, Pearson, Mackenzie, Satapati, Santhosh, Zhou, Heather, McLaren, David G., Previs, Stephen F., Chen, Ying, Qian, Ying, Petrov, Aleksandr, Wu, Margaret, Shen, Xiaolan, Yao, Jun, Nunes, Christian N., Howard, Andrew D., Wang, Liangsu, Erion, Mark D., Rutter, Jared, Holland, William L., Kelley, David E., Summers, Scott A.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26.07.2019; The American Association for the Advancement of Science
• Subjects: Ablation; Adipose tissue; Animals; Backbone; Cardiovascular diseases; Ceramide; Ceramides - chemistry; Ceramides - genetics; Ceramides - metabolism; Coronary artery disease; Desaturase; Diabetes mellitus; Diet; Diet, High-Fat - adverse effects; Disease resistance; Disorders; Enzymes; Fat metabolism; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Gene Deletion; Genetic engineering; Glucose; Glucose metabolism; Heart diseases; High fat diet; Inserts; Insulin; Insulin resistance; Insulin Resistance - genetics; Leptin; Leptin - deficiency; Lipid metabolism; Lipids; Liver; Liver diseases; Membrane Proteins - genetics; Metabolic disorders; Metabolic syndrome; Metabolism; Mice; Mice, Mutant Strains; Nutrient deficiency; Oxidoreductases - genetics; Sphingolipids; Sphingolipids - chemistry; Sphingolipids - metabolism; Steatosis
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aav3722

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.