Endothelin-1 induces lipolysis through activation of the GC/cGMP/Ca2+/ERK/CaMKIII pathway in 3T3-L1 adipocytes |
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| Affiliation: | 1. Institutes of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;2. Department of Life Science, College of Science, Chinese Culture University, Taipei, Taiwan;3. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;4. Division of Cardiology, Cheng-Hsin General Hospital, Taipei, Taiwan;5. Heart Center, Cheng-Hsin General Hospital, Taipei, Taiwan;6. Institute of Biophotonics, College of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan;7. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan;8. College of Human Development and Health, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan;9. Division of Metabolism, Cheng-Hsin General Hospital, Taipei, Taiwan;10. Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan;1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America;2. Shanghai Municipal Center for Disease Control and Prevention, State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, PR China;3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China;1. Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy;2. INBB, National Institute for Biostructures and Biosystems, Viale delle Medaglie d''Oro 305, 00136 Rome, Italy;3. Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden;4. Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy;5. National Cancer Research Center, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy;1. Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;2. Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;3. Project Management Department, Shionogi & Co., Ltd, 8F (Reception) / 9F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan;4. Research Planning Department, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;1. Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan;2. Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan;3. Laboratory of Farm Animal Internal Medicine, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan;4. Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan;5. Laboratory of Veterinary Pharmacology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan |
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| Abstract: | Endothelin-1 (ET-1) is a potent vasoconstrictive peptide produced and secreted mainly by endothelial cells. Recent studies indicate that ET-1 can regulate lipid metabolism, which may increase the risk of insulin resistance. Our previous studies revealed that ET-1 induced lipolysis in adipocytes, but the underlying mechanisms were unclear. 3T3-L1 adipocytes were used to investigate the effect of ET-1 on lipolysis and the underlying mechanisms. Glycerol levels in the incubation medium and hormone-sensitive lipase (HSL) phosphorylation were used as indices for lipolysis. ET-1 significantly increased HSL phosphorylation and lipolysis, which were completely inhibited by ERK inhibitor (PD98059) and guanylyl cyclase (GC) inhibitor (LY83583). LY83583 reduced ET-1-induced ERK phosphorylation. A Ca2+-free medium and PLC inhibitor caused significant decreases in ET-1-induced lipolysis as well as ERK and HSL phosphorylation, and IP3 receptor activator (D-IP3) increased lipolysis. ET-1 increased cGMP production, which was not affected by depletion of extracellular Ca2+. On the other hand, LY83583 diminished the ET-1-induced Ca2+ influx. Transient receptor potential vanilloid-1 (TRPV-1) antagonist and shRNA partially inhibited ET-1-induced lipolysis. ET-1-induced lipolysis was completely suppressed by CaMKIII inhibitor (NH-125). These results indicate that ET-1 stimulates extracellular Ca2+ entry and activates the intracellular PLC/IP3/Ca2+ pathway through a cGMP-dependent pathway. The increased cytosolic Ca2+ that results from ET-1 treatment stimulates ERK and HSL phosphorylation, which subsequently induces lipolysis. ET-1 induces HSL phosphorylation and lipolysis via the GC/cGMP/Ca2+/ERK/CaMKIII signaling pathway in 3T3-L1 adipocytes. |
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