Journal article
Targeting a ceramide double bond improves insulin resistance and hepatic steatosis
Science (American Association for the Advancement of Science), Vol.365(6451), pp.386-392
07/26/2019
DOI: 10.1126/science.aav3722
PMCID: PMC6787918
PMID: 31273070
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.
Details
- Title: Subtitle
- Targeting a ceramide double bond improves insulin resistance and hepatic steatosis
- Creators
- Bhagirath Chaurasia - University of UtahTrevor S Tippetts - University of UtahRafael Mayoral Monibas - Merck Research Laboratories, Merck, Kenilworth, NJ 07033, USAJinqi Liu - MSDYing Li - University of UtahLiping Wang - University of UtahJoseph L Wilkerson - University of UtahC Rufus Sweeney - University of UtahRenato Felipe Pereira - Universidade Estadual Paulista (Unesp)Doris Hissako Sumida - Universidade Estadual Paulista (Unesp)J Alan Maschek - University of UtahJames E Cox - University of UtahVincent Kaddai - University of UtahGraeme Iain Lancaster - Baker Heart and Diabetes InstituteMonowarul Mobin Siddique - Universiti Brunei DarussalamAnnelise Poss - University of UtahMackenzie Pearson - SciexSanthosh Satapati - MSDHeather Zhou - MSDDavid G McLaren - MSDStephen F Previs - MSDYing Chen - MSDYing Qian - MSDAleksandr Petrov - MSDMargaret Wu - MSDXiaolan Shen - MSDJun Yao - MSDChristian N Nunes - Merck Research Laboratories, Merck, Kenilworth, NJ 07033, USAAndrew D Howard - MSDLiangsu Wang - University of UtahMark D Erion - MSDJared Rutter - University of UtahWilliam L Holland - University of UtahDavid E Kelley - MSDScott A Summers - University of Utah
- Resource Type
- Journal article
- Publication Details
- Science (American Association for the Advancement of Science), Vol.365(6451), pp.386-392
- DOI
- 10.1126/science.aav3722
- PMID
- 31273070
- PMCID
- PMC6787918
- ISSN
- 0036-8075
- eISSN
- 1095-9203
- Grant note
- T32 DK091317 / NIDDK NIH HHS R01 DK108833 / NIDDK NIH HHS R43 DK116450 / NIDDK NIH HHS R01 DK115824 / NIDDK NIH HHS R25 DK109894 / NIDDK NIH HHS P30 DK020579 / NIDDK NIH HHS R01 DK112826 / NIDDK NIH HHS UL1 TR001863 / NCATS NIH HHS R44 DK116450 / NIDDK NIH HHS R25 HL108828 / NHLBI NIH HHS R01 DK122001 / NIDDK NIH HHS
- Language
- English
- Date published
- 07/26/2019
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359895902771
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