Eicosapentaenoic acid administration attenuates the pro-inflammatory properties of VLDL by decreasing its susceptibility to lipoprotein lipase in macrophages.
High level of plasma very low-density lipoprotein (VLDL) has been identified as a risk factor for coronary heart disease. Recent evidence suggests that excess VLDL induces inflammatory responses in macrophages and vascular endothelial cells. The Japan EPA Lipid Intervention Study (JELIS), a large scale clinical trial, demonstrated that highly purified eicosapentaenoic acid (EPA) prevented the onset of cardiovascular events in LDL-cholesterol independent fashion. In this study, we investigated the impact of EPA on pro-inflammatory properties of VLDL. Effects of VLDL prepared from mice fed 5% EPA diet for 1 week (EPA-VLDL) or mice fed normal diet (Ctrl-VLDL) on the mRNA expression of pro-inflammatory factors were examined in human THP-1 macrophages. Ctrl-VLDL increased mRNA expression of pro-inflammatory factors such as interleukin-1β and tumor necrosis factor-α in macrophages. In contrast, the increases in pro-inflammatory factors by EPA-VLDL were lower than those by Ctrl-VLDL. Moreover, EPA-VLDL-treated macrophages had less triglyceride accumulation than Ctrl-VLDL-treated macrophages. Inhibition of lipoprotein lipase (LPL) appeared to suppress inflammation and triglyceride accumulation by Ctrl-VLDL suggesting that hydrolysis of VLDL is required for the pro-inflammatory properties of VLDL. Free fatty acid release from EPA-VLDL by macrophages and purified LPL was less than that from Ctrl-VLDL. Extracellular LPL mass was decreased by EPA-VLDL. Taken together, these findings indicate that the pro-inflammatory properties of VLDL were attenuated by EPA administration via decrease in susceptibility of VLDL to LPL. It appears possible that anti-inflammatory effects of EPA on VLDL contribute to the suppression of cardiovascular risk by EPA.
Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Co, Ltd, 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan.
Yasutaka
Y
Jinno
Masanori
M
Nakakuki
Hiroyuki
H
Kawano
Tatsuto
T
Notsu
Kiyoshi
K
Mizuguchi
Kazunori
K
Imada
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053304:Apolipoprotein C-II / Q000097:blood; D053305:Apolipoprotein C-III / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077403:Orlistat; D010316:Particle Size; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D053304:Apolipoprotein C-II; D053305:Apolipoprotein C-III; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D007783:Lactones; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000077403:Orlistat; D015118:Eicosapentaenoic Acid; C548261:LPL protein, human; D008071:Lipoprotein Lipase