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

Abstract

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 TNFa 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.-Wang, L., R. Gill, T. L. Pedersen, L. J. Higgins, J. W. Newman, and J. C. Rutledge. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J. Lipid Res. 2009. 50: 204-213.

Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes

“…In our study, mRNA levels of pro-inflammatory markers IL-6 and MCP-1 were upregulated by hyperoxia. In this context, it has been demonstrated that lipolysis can produce inflammatory responses in endothelial cells [52]; it is therefore possible that FFA may induce the expression of pro-inflammatory markers in 3T3-L1 adipocytes.…”

Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways

“…Our previous studies indicated acute exposure to hydrolyzed TGRLs (TGRL lipolysis products) lead to inflammatory injury in human aortic endothelial cells (22,23,27,28), and we hypothesized similar effects may occur in the vasculature of the brain. In our in vitro model of cultured HBMECs, TEM revealed ultrastructural abnormalities in response to TGRL lipolysis products indicative of lipotoxic injury, including mitochondrial swelling and increased levels of lipid droplets in close proximity to mitochondria at 3 h. To further investigate the particular pathway responsible for this injury, we assayed for production of ROS and detected notably elevated levels of superoxide within 15 min of TGRL lipolysis product treatment that were significantly reduced by concomitant treatment with SOD, suggesting that TGRL lipolysis product-mediated HBMEC injury is dependent, at least in part, on elevated ROS.…”

“…This process results in TGRL remnant particle formation and lipolysis products such as phospholipids and fatty acids. Previous studies have shown that TGRL lipolysis products cause aortic endothelial injury, including inflammation, elevated expression of reactive oxygen species (ROS), and increased vascular permeability (22)(23)(24)(25)(26)(27)(28)(29). Additionally, activating transcription factor (ATF) 3 appears to play an important role as a master regulator of inflammation in the aortic endothelium in response to TGRL lipolysis products (22,30).…”

A Novel Non-agonist Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity

“…It has shown that the products of lipolysis such as fatty acids induce inflammation in adipose tissue (23,24). Therefore, we next analyzed the expression of genes that are associated with lipolysis.…”