ArticleJournal of immunology (Baltimore, Md. : 1950)2023
Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.
Article in Journal of immunology (Baltimore, Md. : 1950), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 24 citations in OpenAlex.
- Modulatory effects of S1QEL on OxLDL-induced metabolic alterations and inflammatory responses in human monocytes.Immunometabolism (Cobham, Surrey) · 2026Article
- Reprogramming of the lipid metabolism axis in systemic sclerosis: mechanism analysis and therapeutic potential.Clinical rheumatology · 2026Review
- NRF2-mediated inhibition of alveolar macrophage MHC II expression during Mycobacterium tuberculosis infection.Cell reports · 2026Article
- Article
- Itaconate alleviates cholesterol burden via ABCA1 stabilization and cholesterol efflux.Atherosclerosis · 2025Article
- Identification and validation of mitochondrial endoplasmic reticulum membrane-related genes in atherosclerosis.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Downregulation of ATP8B2 in atherosclerosis exacerbates foam cell-like pathological changes via impairing lysosomal membrane fusion.Molecular biology reports · 2025Article
- Article
- Co-Targeting Biomimetic Nanoparticles Alleviate Atherosclerosis by Inhibiting the Vicious Circle Between Inflammation and Lipids.International journal of nanomedicine · 2025Article
- Bioinformatic analysis identifies LPL as a critical gene in diabetic kidney disease via lipoprotein metabolism.Frontiers in endocrinology · 2025Article
- Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution.Cell reports · 2024Article
- Investigating the regulatory mechanism of glucose metabolism by ubiquitin-like protein MNSFβ.Molecular biology reports · 2024Article
- Cholesterol accumulation impairs HIF-1α-dependent immunometabolic reprogramming of LPS-stimulated macrophages by upregulating the NRF2 pathway.Scientific reports · 2024Article
- John Yudkin's hypothesis: sugar is a major dietary culprit in the development of cardiovascular disease.Frontiers in nutrition · 2024Review
- The interaction between oral microbiota and gut microbiota in atherosclerosis.Frontiers in cardiovascular medicine · 2024Review
- Fructose overconsumption-induced reprogramming of microglia metabolism and function.Frontiers in immunology · 2024Review
- Article
- Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism.Frontiers in cellular and infection microbiology · 2024Review
- Can the reprogrammed cancer cells serve as an alternative source of (induced) cancer stem cells?Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology · 2024Article
- Measuring the rate of NADPH consumption by glutathione reductase in the cytosol and mitochondria.PloS one · 2024Article
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Authors and funding
19 authors at 4 institutions in 2 countries.
Funding
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 (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. 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 hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (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.
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Registered trials
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