<scp>LPS</scp> stimulation stabilizes <scp>HIF</scp> ‐1α by enhancing <scp>HIF</scp> ‐1α acetylation via the <scp>PARP1‐SIRT1</scp> and <scp>ACLY‐Tip60</scp> pathways in macrophages

Abstract

Abstract Hypoxia and inflammatory mediators stabilize hypoxia‐inducible factor (HIF)‐1α through posttranslational modifications, such as phosphorylation and succinylation. Here, we identified sirtuin 1 (SIRT1) and 60 kDa Tat‐interactive protein (Tip60)‐mediated acetylation as another critical posttranslational modification that regulates HIF‐1α protein stability under lipopolysaccharide (LPS) stimulation. Mechanistically, DNA damage induced by excessive reactive oxygen species (ROS) activated poly (ADP‐ribose) polymerase 1 (PARP1) to consume oxidized nicotinamide adenine dinucleotide (NAD + ). Correspondingly, SIRT1 activity was decreased with the decline in NAD + levels, resulting in increased HIF‐1α acetylation. LPS also activated the ATP‐citrate lyase (ACLY)‐Tip60 pathway to further enhance HIF‐1α acetylation. Acetylation contributed to HIF‐1α stability and exacerbated LPS‐induced inflammation. Thus, inhibiting HIF‐1α stability by decreasing its acetylation could partly alleviate LPS‐induced inflammation. In conclusion, we revealed the mechanism by which LPS stabilized HIF‐1α by increasing its acetylation via the PARP1‐SIRT1 and ACLY‐Tip60 pathways in fish macrophages. This study may provide novel insights for manipulation of HIF‐1α acetylation as a therapeutic strategy against inflammation from the perspective of acetylation in vertebrates.