Targeting a ceramide double bond improves insulin resistance and hepatic steatosis

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Chaurasia, Bhagirath ^{[1, 2]} ; Tippetts, Trevor S. ^{[1, 2]} ; Monibas, Rafael Mayoral ^[3] ; Liu, Jinqi ^{[3, 4]} ; Li, Ying ^{[1, 2]} ; Wang, Liping ^{[1, 2]} ; Wilkerson, Joseph L. ^{[1, 2]} ; Sweeney, C. Rufus ^{[1, 2]} ; Pereira, Renato Felipe ^[5] ; Sumida, Doris Hissako ^[5] ; Maschek, J. Alan ^{[2, 6]} ; Cox, James E. ^{[2, 6]} ; Kaddai, Vincent ^{[1, 2]} ; Lancaster, Graeme Iain ^[7] ; Siddique, Monowarul Mobin ^[8] ; Poss, Annelise ^{[1, 2]} ; Pearson, Mackenzie ^[9] ; Satapati, Santhosh ^[3] ; Zhou, Heather ^[3] ; McLaren, David G. ^[3] ; Previs, Stephen F. ^[3] ; Chen, Ying ^[3] ; Qian, Ying ^[3] ; Petrov, Aleksandr ^[3] ; Wu, Margaret ^[3] ; Shen, Xiaolan ^[3] ; Yao, Jun ^[3] ; Nunes, Christian N. ^[3] ; Howard, Andrew D. ^[3] ; Wang, Liangsu ^{[3, 10]} ; Erion, Mark D. ^{[3, 11]} ; Rutter, Jared ^{[2, 6, 12]} ; Holland, William L. ^{[1, 2]} ; Kelley, David E. ^[3] ; Summers, Scott A. ^{[1, 2]}

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^[1] Univ Utah, Dept Nutr & Integrat Physiol, Salt Lake City, UT 84112 - USA

^[2] Univ Utah, Diabet & Metab Res Ctr, Salt Lake City, UT 84112 - USA

^[3] Merck, Merck Res Labs, Kenilworth, NJ 07033 - USA

^[4] Bristol Myers Squibb, Princeton, NJ 08648 - USA

^[5] Sao Paulo State Univ UNESP, Sch Dent, BR-16015 Aracatuba - Brazil

^[6] Univ Utah, Dept Biochem, Salt Lake City, UT 84112 - USA

^[7] Baker IDI Heart & Diabet Inst, Melbourne, Vic 3004 - Australia

^[8] Univ Brunei Darussalam, Fac Sci, Gadong 1410 - Brunei

^[9] SCIEX Ltd, Framingham, MA 01701 - USA

^[10] Morph Therapeut, Waltham, MA 02451 - USA

^[11] Johnson & Johnson, Spring House, PA 19477 - USA

^[12] Howard Hughes Med Inst, Salt Lake City, UT 84112 - USA

• Tipo de documento: Artigo Científico
• Fonte: Science; v. 365, n. 6451, p. 386+, JUL 26 2019.
• Citações Web of Science: 40

Resumo

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. (AU)

• Processo FAPESP: 14/17619-6 - Estudo dos mecanismos envolvidos no desenvolvimento de resistência à insulina em ratos com lesão periapical
• Beneficiário: Renato Felipe Pereira
• Modalidade de apoio: Bolsas no Brasil - Doutorado