Oxidized LDL accumulation suppresses glycolysis and attenuates the macrophage inflammatory response by diverting transcription from the HIF-1α to the Nrf2 pathway
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ABSTRACT: Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lys2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2 and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 hours with oxidized LDL (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs down-regulated inflammatory, hypoxia and cholesterol metabolism pathways, while antioxidant pathway, fatty acid oxidation and ABC family proteins were up-regulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both HIF-1α stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced Nrf2-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.
ORGANISM(S): Mus musculus
PROVIDER: GSE239696 | GEO | 2023/08/28
REPOSITORIES: GEO
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