Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages

Abstract 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 (HDLHealthy) and patients with re...

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Autores principales:	Shigeyasu Tsuda, Masakazu Shinohara, Toshihiko Oshita, Manabu Nagao, Nobuaki Tanaka, Takeshige Mori, Tetsuya Hara, Yasuhiro Irino, Ryuji Toh, Tatsuro Ishida, Ken-ichi Hirata
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3b7d6c0118994f47908cc9a7e8a96bc3
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spelling	oai:doaj.org-article:3b7d6c0118994f47908cc9a7e8a96bc32021-12-02T15:06:18ZNovel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages10.1038/s41598-017-13154-02045-2322https://doaj.org/article/3b7d6c0118994f47908cc9a7e8a96bc32017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-13154-0https://doaj.org/toc/2045-2322Abstract 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 (HDLHealthy) and patients with recurrent coronary atherosclerotic disease (HDLCAD) 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. HDLHealthy treatment attenuated the pro-inflammatory lipid mediator production, particularly that of leukotriene (LT) B4, and this treatment enhanced lipoxin (LX) B4 and resolvin (Rv) E2 production. HDLHealthy treatment enhanced the proteasome-mediated degradation of the LTB4-producing enzyme 5-lipoxygenase (LO) in activated macrophages; however, HDLCAD did not show these anti-inflammatory effects. HDLHealthy was engulfed by macrophages via clathrin-mediated endocytosis, which was a critical step in 5-LO/LTB4 regulation. We also found that HDLCAD showed higher levels of the LTB4-producing enzymes and thus promoted LTB4 production from HDLCAD. In addition, LTB4 attenuated HDL endocytosis, HDL-mediated 5-LO degradation in macrophages, and HDL-derived augmentation of macrophage phagocytosis. These results indicated that local LTB4 produced de novo from HDLCAD regulates HDL-macrophage functional interactions and plays critical roles in dysfunctional, inflammatory HDL characteristics.Shigeyasu TsudaMasakazu ShinoharaToshihiko OshitaManabu NagaoNobuaki TanakaTakeshige MoriTetsuya HaraYasuhiro IrinoRyuji TohTatsuro IshidaKen-ichi HirataNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shigeyasu Tsuda Masakazu Shinohara Toshihiko Oshita Manabu Nagao Nobuaki Tanaka Takeshige Mori Tetsuya Hara Yasuhiro Irino Ryuji Toh Tatsuro Ishida Ken-ichi Hirata Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages
description	Abstract 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 (HDLHealthy) and patients with recurrent coronary atherosclerotic disease (HDLCAD) 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. HDLHealthy treatment attenuated the pro-inflammatory lipid mediator production, particularly that of leukotriene (LT) B4, and this treatment enhanced lipoxin (LX) B4 and resolvin (Rv) E2 production. HDLHealthy treatment enhanced the proteasome-mediated degradation of the LTB4-producing enzyme 5-lipoxygenase (LO) in activated macrophages; however, HDLCAD did not show these anti-inflammatory effects. HDLHealthy was engulfed by macrophages via clathrin-mediated endocytosis, which was a critical step in 5-LO/LTB4 regulation. We also found that HDLCAD showed higher levels of the LTB4-producing enzymes and thus promoted LTB4 production from HDLCAD. In addition, LTB4 attenuated HDL endocytosis, HDL-mediated 5-LO degradation in macrophages, and HDL-derived augmentation of macrophage phagocytosis. These results indicated that local LTB4 produced de novo from HDLCAD regulates HDL-macrophage functional interactions and plays critical roles in dysfunctional, inflammatory HDL characteristics.
format	article
author	Shigeyasu Tsuda Masakazu Shinohara Toshihiko Oshita Manabu Nagao Nobuaki Tanaka Takeshige Mori Tetsuya Hara Yasuhiro Irino Ryuji Toh Tatsuro Ishida Ken-ichi Hirata
author_facet	Shigeyasu Tsuda Masakazu Shinohara Toshihiko Oshita Manabu Nagao Nobuaki Tanaka Takeshige Mori Tetsuya Hara Yasuhiro Irino Ryuji Toh Tatsuro Ishida Ken-ichi Hirata
author_sort	Shigeyasu Tsuda
title	Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages
title_short	Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages
title_full	Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages
title_fullStr	Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages
title_full_unstemmed	Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages
title_sort	novel mechanism of regulation of the 5-lipoxygenase/leukotriene b4 pathway by high-density lipoprotein in macrophages
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3b7d6c0118994f47908cc9a7e8a96bc3
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Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages

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