| First Author | Ting KKY | Year | 2023 |
| Journal | J Immunol | Volume | 211 |
| Issue | 10 | Pages | 1561-1577 |
| PubMed ID | 37756544 | Mgi Jnum | J:359902 |
| Mgi Id | MGI:7568932 | Doi | 10.4049/jimmunol.2300293 |
| Citation | Ting KKY, et al. (2023) Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1alpha to the Nrf2 Pathway. J Immunol 211(10):1561-1577 |
| abstractText | Lipid accumulation in macrophages (Mphis) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mphi metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mphis and bone marrow-derived Mphis with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mphis 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 Mphis 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 Mphis impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-alpha (HIF-1alpha) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mphis. Intracellular lipid accumulation in Mphis also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1alpha, and Nrf2-deficient Mphis resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1alpha- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1alpha to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mphis with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mphis cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mphis derived from the atherosclerotic mouse and human aorta. |
