In vivo efficacy of acyl CoA: diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia.

Abstract

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.

• Authors: Andrew J King, Jason A Segreti, Kelly J Larson, Andrew J Souers, Philip R Kym, Regina M Reilly, Christine A Collins, Martin J Voorbach, Gang Zhao, Scott W Mittelstadt, Bryan F Cox
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 637 Issue 1-3 Pg. 155-61 (Jul 10 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20385122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• Acyl Coenzyme A
• Enzyme Inhibitors
• Triglycerides
• Corn Oil
• Diacylglycerol O-Acyltransferase

Topics

• Acyl Coenzyme A (metabolism)
• Animals
• Cardiovascular Diseases (prevention & control)
• Corn Oil (pharmacology)
• Cricetinae
• Diacylglycerol O-Acyltransferase (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Hyperlipidemias (blood, drug therapy, enzymology, metabolism)
• Male
• Mice
• Postprandial Period
• Rats
• Risk Factors
• Rodentia (classification)
• Triglycerides (blood, metabolism)