ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2
Yvonne Benatzy,
Megan A. Palmer,
Dieter Lütjohann,
Rei-Ichi Ohno,
Nadja Kampschulte,
Nils Helge Schebb,
Dominik C. Fuhrmann,
Ryan G. Snodgrass,
Bernhard Brüne
Affiliations
Yvonne Benatzy
Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany
Megan A. Palmer
Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany
Dieter Lütjohann
Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
Rei-Ichi Ohno
Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Nadja Kampschulte
Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Nils Helge Schebb
Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
Dominik C. Fuhrmann
Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany; Corresponding author. Goethe University Frankfurt Faculty of Medicine Institute of Biochemistry I Theodor-Stern-Kai 7 60590 Frankfurt, Germany,
Ryan G. Snodgrass
Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany; Western Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Davis, CA, USA; Corresponding author. Western Human Nutrition Research Center (WHNRC), Agricultural Research Service (ARS), United States Department of Agriculture (USDA), 430 West Health Sciences Drive, Davis, CA 95616 USA
Bernhard Brüne
Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Frankfurt, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany; Corresponding author. Goethe University Frankfurt Faculty of Medicine Institute of Biochemistry I Theodor-Stern-Kai 7 60590 Frankfurt, Germany.
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.
