Oxidized Low-Density Lipoprotein Accumulation in Macrophages Impairs Lipopolysaccharide-Induced Activation of AKT2, ATP Citrate Lyase, Acetyl-Coenzyme A Production, and Inflammatory Gene H3K27 Acetylation.

Content Provider	Europe PMC
Author	Ting, Kenneth K. Y. Yu, Pei Iyayi, Mudia Dow, Riley Hyduk, Sharon J. Floro, Eric Ibrahim, Hisham Karim, Saraf Polenz, Chanele K. Winer, Daniel A. Woo, Minna Rocheleau, Jonathan Jongstra-Bilen, Jenny Cybulsky, Myron I.
Copyright Year	2024
Abstract	AbstractThe accumulation of lipid and the formation of macrophage foam cells is a hallmark of atherosclerosis, a chronic inflammatory disease. To better understand the role of macrophage lipid accumulation in inflammation during atherogenesis, we studied early molecular events that follow the accumulation of oxidized low-density lipoprotein (oxLDL) in cultured mouse macrophages. We previously showed that oxLDL accumulation downregulates the inflammatory response in conjunction with downregulation of late-phase glycolysis. In this study, we show that within hours after LPS stimulation, macrophages with accumulated oxLDL maintain early-phase glycolysis but selectively downregulate activation of AKT2, one of three AKT isoforms. The inhibition of AKT2 activation reduced LPS-induced ATP citrate lyase activation, acetyl-CoA production, and acetylation of histone 3 lysine 27 (H3K27ac) in certain inflammatory gene promoters. In contrast to oxLDL, multiple early LPS-induced signaling pathways were inhibited in macrophages with accumulated cholesterol, including TBK1, AKT1, AKT2, MAPK, and NF-κB, and early-phase glycolysis. The selective inhibition of LPS-induced AKT2 activation was dependent on the generation of mitochondrial oxygen radicals during the accumulation of oxLDL in macrophages prior to LPS stimulation. This is consistent with increased oxidative phosphorylation, fatty acid synthesis, and oxidation pathways found by comparative transcriptomic analyses of oxLDL-loaded versus control macrophages. Our study shows a functional connection between oxLDL accumulation, inactivation of AKT2, and the inhibition of certain inflammatory genes through epigenetic changes that occur soon after LPS stimulation, independent of early-phase glycolysis.
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Page Count	17
Volume Number	8
DOI	10.4049/immunohorizons.2300101
PubMed Central reference number	PMC10835650
Issue Number	1
PubMed reference number	38193847
Journal	ImmunoHorizons
e-ISSN	25737732
Language	English
Publisher	AAI
Publisher Date	2024-01-01
Access Restriction	Open
Rights License	This article is distributed under the terms of the CC BY 4.0 Unported license. Copyright © 2024 The Authors
Content Type	Text
Resource Type	Article
Subject	Immunology Immunology and Allergy