ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2

Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced p...

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Veröffentlicht in:Redox biology 2024-06, Vol.72, p.103149, Article 103149
Hauptverfasser: Benatzy, Yvonne, Palmer, Megan A., Lütjohann, Dieter, Ohno, Rei-Ichi, Kampschulte, Nadja, Schebb, Nils Helge, Fuhrmann, Dominik C., Snodgrass, Ryan G., Brüne, Bernhard
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Sprache:eng
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Zusammenfassung:Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation. [Display omitted] •Suppressing macrophage ALOX15B extensively reduced SREBP2-target genes.•Silencing ALOX15B decreased sterol intermediates and oxysterols in macrophages.•ALOX15B-suppression lowered macrophage lipid peroxidation (LPO) and oxylipins.•LPO controls macrophage ERK1/2 activation and SREBP2-target gene expression.•Macrophage cholesterol homeostasis is regulated by an ALOX15B–LPO–ERK1/2–SREBP2 axis.
ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2024.103149