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.