期刊
FASEB JOURNAL
卷 36, 期 7, 页码 -出版社
WILEY
DOI: 10.1096/fj.202200256R
关键词
acetylation; HIF-1 alpha; LPS; NAD(+); ROS
资金
- Agriculture Research System of China (China's Agricultural Research System) [CARS-47-11]
- National Natural Science Foundation of China-Shandong Joint Fund (NSFC-Shandong Joint Fund) [U2106232]
- NSFC \ Key Programme [31830103]
- Scientific and Technological Innovation of Blue Granary [2018YFD0900402]
- Ten-thousand Talents Program [2018-29]
In this study, we revealed the mechanism by which LPS stabilizes HIF-1α by increasing its acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways, and found that reducing HIF-1α acetylation could alleviate LPS-induced inflammation.
Hypoxia and inflammatory mediators stabilize hypoxia-inducible factor (HIF)-1 alpha 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-1 alpha 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-1 alpha acetylation. LPS also activated the ATP-citrate lyase (ACLY)-Tip60 pathway to further enhance HIF-1 alpha acetylation. Acetylation contributed to HIF-1 alpha stability and exacerbated LPS-induced inflammation. Thus, inhibiting HIF-1 alpha stability by decreasing its acetylation could partly alleviate LPS-induced inflammation. In conclusion, we revealed the mechanism by which LPS stabilized HIF-1 alpha 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-1 alpha acetylation as a therapeutic strategy against inflammation from the perspective of acetylation in vertebrates.
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