| Literature DB >> 31273070 |
Bhagirath Chaurasia1, Trevor S Tippetts1, Rafael Mayoral Monibas2, Jinqi Liu2, Ying Li1, Liping Wang1, Joseph L Wilkerson1, C Rufus Sweeney1, Renato Felipe Pereira3, Doris Hissako Sumida3, J Alan Maschek4, James E Cox4, Vincent Kaddai1, Graeme Iain Lancaster5, Monowarul Mobin Siddique6, Annelise Poss1, Mackenzie Pearson7, Santhosh Satapati2, Heather Zhou2, David G McLaren2, Stephen F Previs2, Ying Chen2, Ying Qian2, Aleksandr Petrov2, Margaret Wu2, Xiaolan Shen2, Jun Yao2, Christian N Nunes2, Andrew D Howard2, Liangsu Wang2, Mark D Erion2, Jared Rutter4,8, William L Holland1, David E Kelley2, Scott A Summers9.
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.Entities:
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Year: 2019 PMID： 31273070 PMCID： PMC6787918 DOI： 10.1126/science.aav3722
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728