Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B pathway by high-density lipoprotein in macrophages.

High-density lipoprotein (HDL) interacts with various cells, particularly macrophages, in functional cell-HDL interactions. Here, we found that HDL protein quality and lipid quality play critical roles in HDL functions. HDL fractions from healthy volunteers (HDL) and patients with recurrent coronary atherosclerotic disease (HDL) were prepared. To analyse functional HDL-macrophage interactions, macrophages were co-incubated with each HDL, and lipid mediator production was assessed by liquid chromatography/mass spectrometry-based metabololipidomics. HDL treatment attenuated the pro-inflammatory lipid mediator production, particularly that of leukotriene (LT) B, and this treatment enhanced lipoxin (LX) B and resolvin (Rv) E2 production. HDL treatment enhanced the proteasome-mediated degradation of the LTB-producing enzyme 5-lipoxygenase (LO) in activated macrophages; however, HDL did not show these anti-inflammatory effects. HDL was engulfed by macrophages via clathrin-mediated endocytosis, which was a critical step in 5-LO/LTB regulation. We also found that HDL showed higher levels of the LTB-producing enzymes and thus promoted LTB production from HDL. In addition, LTB attenuated HDL endocytosis, HDL-mediated 5-LO degradation in macrophages, and HDL-derived augmentation of macrophage phagocytosis. These results indicated that local LTB produced de novo from HDL regulates HDL-macrophage functional interactions and plays critical roles in dysfunctional, inflammatory HDL characteristics.