Diacylglycerol acyltransferase 1 inhibition lowers serum triglycerides in the Zucker fatty rat and the hyperlipidemic hamster.
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.
King
Andrew J
AJ
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. andrew.j.king@abbott.com
Segreti
Jason A
JA
Larson
Kelly J
KJ
Souers
Andrew J
AJ
Kym
Philip R
PR
Reilly
Regina M
RM
Zhao
Gang
G
Mittelstadt
Scott W
SW
Cox
Bryan F
BF
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood*
C542909:(IR,2R)-2-(4'-(3-phenyl-ureido)-biphenyl-4-carbonyl)cyclopentanecarboxylic acid; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D014280:Triglycerides; D051048:Diacylglycerol O-Acyltransferase