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Journal of Lipid Research, Vol. 47, 1406-1415, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

Viswanathan Saraswathi and Alyssa H. Hasty¹

Vanderbilt University Medical Center, Department of Molecular Physiology and Biophysics, Nashville, TN 37232

Published, JLR Papers in Press, April 25, 2006.

¹ To whom correspondence should be addressed. e-mail: 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 proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 µg/ml VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular TGs and FFAs, respectively (P < 0.05). The inflammatory proteins tumor necrosis factor-, interleukin-1ß, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1 (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 the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1 gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.

Abbreviations: CE, cholesteryl ester; ERK, extracellular signal-regulated kinase; IL, interleukin; LRP, low density lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; mmLDL, minimally modified low density lipoprotein; PBMC, peripheral blood mononuclear cell; SAPK/JNK, stress-activated protein kinase/c-Jun NH2-terminal kinase; TG, triglyceride; TNF, tumor necrosis factor

Supplementary key words inflammation • gene expression • mitogen-activated protein kinases

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