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Papers In Press, published online ahead of print April 25, 2006
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Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0615
Corresponding Author: alyssa.hasty{at}vanderbilt.edu
Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and pro-inflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride-rich very low density lipoprotein (VLDL)–induced lipid accumulation on macrophage pro-inflammatory processes. Incubation of mouse peritoneal macrophages with 100
Accepted on April 25, 2006
The role of lipolysis in mediating the pro-inflammatory effects of very low density lipoproteins in mouse peritoneal macrophages
g/ml of VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular triglycerides (TGs) and free fatty acids (FFAs), respectively (P<0.05). The inflammatory proteins TNF-
, IL-1
, MCP-1, ICAM-1, MMP3, and MIP-1 were all upregulated by at least 2-fold (P<0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with phosphorylation of MAPK pathway members ERK1/2, SAPK/JNK, and p38 MAPK, and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular triglyceride hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by amelioration of ERK1/2 phosphorylation and MIP-1 gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFA and TG, plays a substantive role in mediating the pro-inflammatory effects of VLDL. These data have important implication for direct pro-atherogenic effects of VLDL on macrophage-driven atherosclerosis.
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