TY - JOUR
T1 - Targeting a ceramide double bond improves insulin resistance and hepatic steatosis
AU - Chaurasia, Bhagirath
AU - Tippetts, Trevor S.
AU - Monibas, Rafael Mayoral
AU - Liu, Jinqi
AU - Li, Ying
AU - Wang, Liping
AU - Wilkerson, Joseph L.
AU - Rufus Sweeney, C.
AU - Pereira, Renato Felipe
AU - Sumida, Doris Hissako
AU - Alan Maschek, J.
AU - Cox, James E.
AU - Kaddai, Vincent
AU - Lancaster, Graeme Iain
AU - Siddique, Monowarul Mobin
AU - Poss, Annelise
AU - Pearson, Mackenzie
AU - Satapati, Santhosh
AU - Zhou, Heather
AU - McLaren, David G.
AU - Previs, Stephen F.
AU - Chen, Ying
AU - Qian, Ying
AU - Petrov, Aleksandr
AU - Wu, Margaret
AU - Shen, Xiaolan
AU - Yao, Jun
AU - Nunes, Christian N.
AU - Howard, Andrew D.
AU - Wang, Liangsu
AU - Erion, Mark D.
AU - Rutter, Jared
AU - Holland, William L.
AU - Kelley, David E.
AU - Summers, Scott A.
N1 - Funding Information:
The authors receive research support from the National Institutes of Health (DK112826 and DK108833 to W.L.H. and DK115824 and DK116450 to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B to W.L.H.), the American Diabetes Association (S.A.S.), the American Heart Association (S.A.S.), the Margolis Foundation (S.A.S.), and the USDA (2019-67018-29250 to B.C.). B.C. received a pilot grant from the Diabetes Research Center at Washington University in St. Louis of the NIH under award number P30DK020579. R.F.P. received a doctoral fellowship from FAPESP (process number 2014/17619-6). T.S.T. and J.L.W. received support from the NIH through the Ruth L. Kirschstein National Research Service Award 5T32DK091317. Studies conducted at Merck Research Laboratories in Kenilworth, NJ, were supported by Merck & Co., Inc.
Publisher Copyright:
© 2019 American Association for the Advancement of Science. All rights reserved.
PY - 2019/7/26
Y1 - 2019/7/26
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aav3722
DO - 10.1126/science.aav3722
M3 - Article
C2 - 31273070
AN - SCOPUS:85068990454
SN - 0036-8075
VL - 365
SP - 386
EP - 392
JO - Science
JF - Science
IS - 6451
ER -