Lipotoxic effects of triacylglycerols in J774.2 macrophages.
OBJECTIVE
Triacylglycerols (TGs) are being considered as an independent risk factor in atherosclerosis and metabolic syndrome, acting by dysregulation of the TG/high-density lipoprotein axis. Accumulation of lipids in subendothelial space attracts macrophages, leading to atherosclerotic plaque formation and increased plaque instability due to formation of foam cells and macrophage death. The aim of this study was to evaluate lipotoxic effects in macrophages caused by TG uptake.


METHODS
J774.2 macrophages were exposed to soybean or olive oil-based lipid emulsions as a source of TGs (1 mg/mL) in a presence or absence of lipase inhibitor paraoxon (20 microM) or to bovine serum albumin-complexed palmitic (150 microM), linoleic (600 microM), and oleic (600 microM) fatty acids.


RESULTS
The results demonstrated accumulation of TGs, G1/S arrest, and cell death with necrotic morphologic features after exposure to TG emulsions. These effects were prevented by treatment with an antioxidant N-acetyl-cysteine (0.5 mM). Paraoxon inhibited intracellular TG degradation but did not prevent lipotoxicity and cell death. Olive oil TG triggered macrophage death in a manner similar to soybean oil. Treatment of the macrophages with free fatty acid, mainly with palmitic acid, showed a reactive oxygen species-independent cell death pathway, which was different from that of TG and was not prevented by N-acetyl-cysteine.


CONCLUSIONS
This study shows a direct lipotoxic pathway for TG molecules in macrophages, which is not associated with degradation of TG molecule to free fatty acids. This study for the first time can explain at a cellular level how TGs as an independent risk factor aggravate atherosclerotic outcomes.
Aronis
Anna
A
School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot, Israel.
Madar
Zecharia
Z
Tirosh
Oren
O
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death; D002460:Cell Line; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D019301:Oleic Acid / Q000494:pharmacology; D000069463:Olive Oil; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology; D010938:Plant Oils; D017382:Reactive Oxygen Species; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013024:Soybean Oil; D013997:Time Factors; D014280:Triglycerides / Q000494:pharmacology*
D000069463:Olive Oil; D010938:Plant Oils; D017382:Reactive Oxygen Species; D014280:Triglycerides; D012710:Serum Albumin, Bovine; D019301:Oleic Acid; D019308:Palmitic Acid; D013024:Soybean Oil; D004247:DNA; D019787:Linoleic Acid; D010261:Paraoxon