The use of stable-isotopically labeled oleic acid to interrogate lipid assembly in vivo: assessing pharmacological effects in preclinical species |
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Authors: | McLaren David G He Timothy Wang Sheng-Ping Mendoza Vivienne Rosa Raymond Gagen Karen Bhat Gowri Herath Kithsiri Miller Paul L Stribling Sloan Taggart Andrew Imbriglio Jason Liu Jinqi Chen Dunlu Pinto Shirly Balkovec James M Devita Robert J Marsh Donald J Castro-Perez Jose M Strack Alison Johns Douglas G Previs Stephen F Hubbard Brian K Roddy Thomas P |
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Institution: | Merck Research Laboratories, Merck & Co., Inc. Rahway, NJ, USA. David_McLaren@merck.com |
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Abstract: | The use of stable isotopically labeled substrates and analysis by mass spectrometry have provided substantial insight into rates of synthesis, disposition, and utilization of lipids in vivo. The information to be gained from such studies is of particular benefit to therapeutic research where the underlying causes of disease may be related to the production and utilization of lipids. When studying biology through the use of isotope tracers, care must be exercised in interpreting the data to ensure that any response observed can truly be interpreted as biological and not as an artifact of the experimental design or a dilutional effect on the isotope. We studied the effects of dosing route and tracer concentration on the mass isotopomer distribution profile as well as the action of selective inhibitors of microsomal tri-glyceride transfer protein (MTP) in mice and diacylglycerol acyltransferase 1 (DGAT1) in nonhuman primates, using a stable-isotopically labeled approach. Subjects were treated with inhibitor and subsequently given a dose of uniformly 13C-labeled oleic acid. Samples were analyzed using a rapid LC-MS technique, allowing the effects of the intervention on the assembly and disposition of triglycerides, cholesteryl esters, and phospholipids to be determined in a single 3 min run from just 10 μl of plasma. |
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Keywords: | cholesteryl ester diacylglycerol acyltransferase fatty acid liquid chromatography-mass spectrometry mass isotopomer distribution analysis microsomal triglyceride transfer protein nonhuman primate phosphatidylcholine stable isotope tracer triglycerides |
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