Benatzy, YvonneYvonneBenatzyPalmer, Megan A.Megan A.PalmerLütjohann, DieterDieterLütjohannOhno, ReiichiReiichiOhnoKampschulte, NadjaNadjaKampschulteSchebb, Nils HelgeNils HelgeSchebbFuhrmann, Dominik ChristianDominik ChristianFuhrmannSnodgrass, Ryan G.Ryan G.SnodgrassBrüne, BernhardBernhardBrüne2024-09-042024-09-042024https://publica.fraunhofer.de/handle/publica/47442110.1016/j.redox.2024.1031492-s2.0-8518950576338581859Macrophage 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.enopen access15-LO2Arachidonate 15-lipoxygenase type BLipid peroxidationMAPKReactive oxygen speciesSterol regulatory element-binding protein 2journal article