出版社：American Society for Biochemistry and Molecular Biology
摘要：Hypertriglyceridemia is an important risk factor for atherosclerosis,especially in obesity. Macrophages are one of the primary celltypes involved in atherogenesis and are thought to contributeto lesion formation through both lipid accumulation and proinflammatorygene expression. In this study, we sought to determine the directimpact of triglyceride (TG)-rich VLDL-induced lipid accumulationon macrophage proinflammatory processes. Incubation of mouseperitoneal macrophages with 100 µg/ml VLDL for 6 h ledto 2.8- and 3.7-fold increases in intracellular TGs and FFAs,respectively (P < 0.05). The inflammatory proteins tumornecrosis factor-, interleukin-1ß, monocyte chemoattractantprotein-1, intercellular adhesion molecule-1, matrix metalloproteinase3 (MMP3), and macrophage inflammatory protein-1 (MIP-1) wereall upregulated by at least 2-fold (P < 0.05) in a dose-dependentmanner in VLDL-treated macrophages. The increase in inflammatorygene expression coincided with the phosphorylation of the mitogen-activatedprotein kinase (MAPK) pathway members extracellular signal-regulatedkinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminalkinase, and p38 MAPK and was ameliorated by U0126, an inhibitorof ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin(Orlistat) resulted in the absence of intracellular TG and FFAaccumulation and was accompanied by the amelioration of ERK1/2phosphorylation and MIP-1 gene expression. These data indicatethat VLDL hydrolysis, and the subsequent accumulation of intracellularFFAs and TGs, plays a substantive role in mediating the proinflammatoryeffects of VLDL. These data have important implications forthe direct proatherogenic effects of VLDL on macrophage-drivenatherosclerosis.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
, interleukin-1ß, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1
