The use of stable-isotopically labeled oleic acid to interrogate lipid assembly in vivo: assessing pharmacological effects in preclinical species

Journal of Lipid Research

Douglas G. Johns¹  Shirly Pinto¹  Jinqi Liu¹  Sheng-Ping Wang¹  Brian K. Hubbard¹  Raymond Rosa¹  Paul L. Miller¹  Andrew Taggart¹  Robert J. DeVita¹  Jose M. Castro-Perez¹  Gowri Bhat¹  Timothy He²  Kithsiri Herath³  Donald J. Marsh³  Sloan Stribling³  Jason Imbriglio³  Stephen F. Previs³  Vivienne Mendoza³  James M. Balkovec³  Dunlu Chen³  Alison Strack³  Karen Gagen³  Thomas P. Roddy³  David G. McLaren⁴ 

[1] Co., Inc. Rahway, NJ;;Merck Research Laboratories, Merck &;Merck Research Laboratories, Merck &To whom correspondence should be addressed. [e-mail];

关键词: cholesteryl ester;    diacylglycerol acyltransferase;    fatty acid;    liquid chromatography-mass spectrometry;    mass isotopomer distribution analysis;    microsomal triglyceride transfer protein;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 tri­glyceride 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.

【 授权许可】

Unknown