PT - JOURNAL ARTICLE AU - Andrew J. King AU - Jason A. Segreti AU - Kelly J. Larson AU - Andrew J. Souers AU - Philip R. Kym AU - Regina M. Reilly AU - Gang Zhao AU - Scott W. Mittelstadt AU - Bryan F. Cox TI - Diacylglycerol Acyltransferase 1 Inhibition Lowers Serum Triglycerides in the Zucker Fatty Rat and the Hyperlipidemic Hamster AID - 10.1124/jpet.109.154047 DP - 2009 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 526--531 VI - 330 IP - 2 4099 - http://jpet.aspetjournals.org/content/330/2/526.short 4100 - http://jpet.aspetjournals.org/content/330/2/526.full SO - J Pharmacol Exp Ther2009 Aug 01; 330 AB - Acyl CoA/diacylglycerol acyltransferase (DGAT) 1 is one of two known DGAT enzymes that catalyze the final and only committed step in triglyceride biosynthesis. The purpose of this study was to test the hypothesis that chronic inhibition of DGAT-1 with a small-molecule inhibitor will reduce serum triglyceride concentrations in both genetic and diet-induced models of hypertriglyceridemia. Zucker fatty rats and diet-induced dyslipidemic hamsters were dosed orally with A-922500 (0.03, 0.3, and 3-mg/kg), a potent and selective DGAT-1 inhibitor, for 14 days. Serum triglycerides were significantly reduced by the 3 mg/kg dose of the DGAT-1 inhibitor in both the Zucker fatty rat (39%) and hyperlipidemic hamster (53%). These serum triglyceride changes were accompanied by significant reductions in free fatty acid levels by 32% in the Zucker fatty rat and 55% in the hyperlipidemic hamster. In addition, high-density lipoprotein-cholesterol was significantly increased (25%) in the Zucker fatty rat by A-922500 administered at 3 mg/kg. This study provides the first report that inhibition of DGAT-1, the final and only committed step of triglyceride synthesis, with a selective small-molecule inhibitor, significantly reduces serum triglyceride levels in both genetic and diet-induced animal models of hypertriglyceridemia. The results of this study support further investigation of DGAT-1 inhibition as a novel therapeutic approach to the treatment of hypertriglyceridemia in humans, and they suggest that inhibition of triglyceride synthesis may have more diverse beneficial effects on serum lipid profiles beyond triglyceride lowering. The American Society for Pharmacology and Experimental Therapeutics