| First Author | Ting KKY | Year | 2024 |
| Journal | Sci Rep | Volume | 14 |
| Issue | 1 | Pages | 11162 |
| PubMed ID | 38750095 | Mgi Jnum | J:355438 |
| Mgi Id | MGI:7640955 | Doi | 10.1038/s41598-024-61493-6 |
| Citation | Ting KKY, et al. (2024) Cholesterol accumulation impairs HIF-1alpha-dependent immunometabolic reprogramming of LPS-stimulated macrophages by upregulating the NRF2 pathway. Sci Rep 14(1):11162 |
| abstractText | Lipid accumulation in macrophages (Mphis) is a hallmark of atherosclerosis. Yet, how lipid loading modulates Mphi inflammatory responses remains unclear. We endeavored to gain mechanistic insights into how pre-loading with free cholesterol modulates Mphi metabolism upon LPS-induced TLR4 signaling. We found that activities of prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH) are higher in cholesterol loaded Mphis post-LPS stimulation, resulting in impaired HIF-1alpha stability, transactivation capacity and glycolysis. In RAW264.7 cells expressing mutated HIF-1alpha proteins resistant to PHDs and FIH activities, cholesterol loading failed to suppress HIF-1alpha function. Cholesterol accumulation induced oxidative stress that enhanced NRF2 protein stability and triggered a NRF2-mediated antioxidative response prior to and in conjunction with LPS stimulation. LPS stimulation increased NRF2 mRNA and protein expression, but it did not enhance NRF2 protein stability further. NRF2 deficiency in Mphis alleviated the inhibitory effects of cholesterol loading on HIF-1alpha function. Mutated KEAP1 proteins defective in redox sensing expressed in RAW264.7 cells partially reversed the effects of cholesterol loading on NRF2 activation. Collectively, we showed that cholesterol accumulation in Mphis induces oxidative stress and NRF2 stabilization, which when combined with LPS-induced NRF2 expression leads to enhanced NRF2-mediated transcription that ultimately impairs HIF-1alpha-dependent glycolytic and inflammatory responses. |
