In vivo efficacy of acyl CoA: diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia.
Postprandial serum triglyceride concentrations have recently been identified as a major, independent risk factor for future cardiovascular events. As a result, postprandial hyperlipidemia has emerged as a potential therapeutic target. The purpose of this study was two-fold. Firstly, to describe and characterize a standardized model of postprandial hyperlipidemia in multiple rodent species; and secondly, apply these rodent models to the evaluation of a novel class of pharmacologic agent; acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitors. Serum triglycerides were measured before and for 4h after oral administration of a standardized volume of corn oil, to fasted C57BL/6, ob/ob, apoE(-/-) and CD-1 mice; Sprague-Dawley and JCR/LA-cp rats; and normolipidemic and hyperlipidemic hamsters. Intragastric administration of corn oil increased serum triglycerides in all animals evaluated, however the magnitude and time-course of the postprandial triglyceride excursion varied. The potent and selective DGAT-1 inhibitor A-922500 (0.03, 0.3 and 3 mg/kg, p.o.), dose-dependently attenuated the maximal postprandial rise in serum triglyceride concentrations in all species tested. At the highest dose of DGAT-1 inhibitor, the postprandial triglyceride response was abolished. This study provides a comprehensive characterization of the time-course of postprandial hyperlipidemia in rodents. In addition, the ability of DGAT-1 inhibitors to attenuate postprandial hyperlipidemia in multiple rodent models, including those that feature insulin resistance, is documented. Exaggerated postprandial hyperlipidemia is inherent to insulin-resistant states in humans and contributes to the substantially elevated cardiovascular risk observed in these patients. Therefore, by attenuating postprandial hyperlipidemia, DGAT-1 inhibition may represent a novel therapeutic approach to reduce cardiovascular risk.
King
Andrew J
AJ
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
Collins
Christine A
CA
Voorbach
Martin J
MJ
Zhao
Gang
G
Mittelstadt
Scott W
SW
Cox
Bryan F
BF
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000517:prevention & control; D003314:Corn Oil / Q000494:pharmacology; D006224:Cricetinae; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D019518:Postprandial Period; D051381:Rats; D012307:Risk Factors; D012377:Rodentia / Q000145:classification; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D000214:Acyl Coenzyme A; D004791:Enzyme Inhibitors; D014280:Triglycerides; D003314:Corn Oil; D051048:Diacylglycerol O-Acyltransferase