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Journal of Lipid Research, Vol. 50, 204-213, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation^*

Limin Wang^1,*, Rajan Gill^,, Theresa L. Pedersen^**, Laura J. Higgins^*, John W. Newman^,** and John C. Rutledge^*

^* Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, University of California, Davis, Davis, CA
Department of Internal Medicine, Department of Nutrition, University of California, Davis, Davis, CA
Department of Entomology, University of California, Davis, Davis, CA
^** United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA

^* This study was supported by National Institutes of Health Grants HL-78615 and HL-55665 and the Richard A. and Nora Eccles Harrison Endowed Chair in Diabetes Research. Additional support for this research was provided by United States Department of Agriculture Agricultural Research Service Project #5306-51530-016-00D, and by National Institute of Environmental Health Sciences Grant P42 ES04699.

Published, JLR Papers in Press, September 23, 2008.

¹ To whom correspondence should be addressed. e-mail: lwang{at}ucdavis.edu

Triglyceride-rich lipoprotein (TGRL) lipolysis products provide a pro-inflammatory stimulus that can alter endothelial barrier function. To probe the mechanism of this lipolysis-induced event, we evaluated the pro-inflammatory potential of lipid classes derived from human postprandial TGRL by lipoprotein lipase (LpL). Incubation of TGRL with LpL for 30 min increased the saturated and unsaturated FFA content of the incubation solutions significantly. Furthermore, concentrations of the hydroxylated linoleates 9-hydroxy ocatadecadienoic acid (9-HODE) and 13-HODE were elevated by LpL lipolysis, more than other measured oxylipids. The FFA fractions elicited pro-inflammatory responses inducing TNF and intracellular adhesion molecule expression and reactive oxygen species (ROS) production in human aortic endothelial cells (HAECs). The FFA-mediated increase in ROS was blocked by both the cytochrome P450 2C9 inhibitor sulfaphenazole and NADPH oxidase inhibitors. Compared with linoleate, 13-HODE was found to be a more potent inducer of ROS production in HAECs, an activity that was insensitive to both NADPH oxidase and cytochrome P450 inhibitors. Therefore, although the oxidative metabolism of FFA in endothelial cells can produce inflammatory responses, TGRL lipolysis can also release preformed mediators of oxidative stress (e.g., HODEs) that may influence endothelial cell function in vivo by stimulating intracellular ROS production.

Supplementary key words endothelial dysfunction • fatty acids • oxidized lipids

Abbreviations: AA, arachidonic acid; apoB, apolipoprotein B; BHT, butylated hydroxytoluene; CM, chylomicron; DCFDA, dichlorofluorescein diacetate; DHA, docosahexaenoic acid; EFA, esterified fatty acid; DPI, diphenylene iodonium; EPA, eicosapentaenoic acid; FAME, fatty acid methyl ester; HAEC, human aortic endothelial cell; HETE, hydroxy eicosatetraenoic acid; HODE, hydroxy ocatadecadienoic acid; ICAM, intracellular adhesion molecule; LA, linoleic acid; LpL, lipoprotein lipase; MG, monoacylglycerol; ROS, reactive oxygen species; SFA, saturated fatty acid; TGRL, triglyceride-rich lipoprotein

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