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Title:   Author  item
                                            WANG, LIMIN - UC DAVIS, INTERNAL MED.item
                                            GILL, RAJAN - UC DAVIS, ENTOMOLOGY,NUTRitem
                                            Pedersen, Theresaitem
                                            HIGGINS, LAURA - UC DAVIS, INTERNAL MED.item
                                            Newman, Johnitem
                                            RUTLEDGE, JOHN - UC DAVIS, INTERNAL MED.
  Submitted to: Journal of Lipid Research
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 9/23/2008
                                    Publication  Date: 11/5/2008
                                    Citation: Wang, L., Gill, R., Pedersen, T.L., Higgins, L.J., Newman, J.W., Rutledge, J.C. 2008. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized free fatty acids that induce endothelial cell inflammation. Journal of Lipid Research.  Papers in press published ahead of print, doi:10.1194/jlr.M700505-JLR200Interpretive Summary: After ingesting a meal, circulating levels of triglyceride rich lipoprotein particles (TGRL) increase, and enzymatic release of lipids in these particles provide a pro-inflammatory stimulus to the surface of the vasculature which may alter its barrier function. This study investigated the mechanisms of this lipolysis-induced dysfunction by exploring the interactions of lipoprotein lipase (LpL) with human postprandial TGRL. Incubation of TGRL with LpL increased the free fatty acid (FFA) content of incubation solutions by 10-fold, including the hydroxy-linoleates 9- and 13-HODE. The FFA fractions produced a variety of LpL-mediated pro-inflammatory responses in human aortic endothelial cells (HAEC). This included increased cytokine production, adhesion molecule expression, and reactive oxygen species (ROS) generation. The FFA-mediated ROS generation was blocked by the pharmacological inhibitors of cytochrome P450 2C9 and NADPH oxidase. As compared to linoleate, 13-HODE was a more potent inducer of ROS production in HAEC cells, an activity that was insensitive to both NADPH oxidase and cytochrome P450 inhibitors. It was concluded from this study that, while the oxidative metabolism of FFA in endothelial cells can produce inflammatory responses, TGRL lipolysis products appear to contain pre-formed mediators of oxidative stress, which may facilitate endothelial cell injury in vivo by stimulating intracellular ROS production.
                                Technical Abstract: Objective–Increased products of triglyceride-rich lipoprotein (TGRL) lipolysis provide a pro-inflammatory stimulus that may alter endothelial barrier function. To probe the mechanism of this lipolysis-induced dysfunction, we evaluated the pro-inflammatory potential of lipid classes derived from human postprandial TGRL by lipoprotein lipase (LpL).  
Methods and Results– Incubation of TGRL with LpL increased the free fatty acid (FFA) content of incubation solutions 10-fold, and produced a ~3-fold increase in linoleic and arachidonic acids.  Furthermore, concentrations of hydroxy-linoleates, 9- and 13-HODE, were elevated ~10-fold by LpL lipolysis, more than other measured oxylipids. The FFA fractions displayed pro-inflammatory activity, inducing TNF' and ICAM expression and reactive oxygen species (ROS) production in human aortic endothelial cells (HAEC). The FFA-mediated increase in ROS was blocked by the cytochrome P450 2C9 inhibitor sulfaphenazole or NADPH oxidase inhibitors.  Compared to linoleate, 13-HODE was found to be a more potent inducer of ROS production in HAEC cells, an activity that was insensitive to both NADPH oxidase and cytochrome P450 inhibitors. 
Conclusions– while the oxidative metabolism of FFA in endothelial cells can produce inflammatory responses, TGRL lipolysis products appear to contain pre-formed mediators of oxidative stress, which may facilitate endothelial cell injury in vivo by stimulating intracellular ROS production.


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