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Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor |
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| Authors: | Zhao Gang Souers Andrew J Voorbach Martin Falls H Doug Droz Brian Brodjian Sevan Lau Yau Yi Iyengar Rajesh R Gao Ju Judd Andrew S Wagaw Seble H Ravn Matthew M Engstrom Kenneth M Lynch John K Mulhern Mathew M Freeman Jennifer Dayton Brian D Wang Xiaojun Grihalde Nelson Fry Dennis Beno David W A Marsh Kennan C Su Zhi Diaz Gilbert J Collins Christine A Sham Hing Reilly Regina M Brune Michael E Kym Philip R |
| Affiliation: | Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064, USA. |
| Abstract: | A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice. |
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