Ligand-activated peroxisome proliferator-activated receptor-δ and -γ inhibit lipopolysaccharide-primed release of high mobility group box 1 through upregulation of SIRT1.
Ligand-activated peroxisome proliferator-activated receptor-δ and -γ inhibit lipopolysaccharide-primed release of high mobility group box 1 through upregulation of SIRT1.
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DOI：
10.1038/cddis.2014.406
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发表时间：
2014-10-02
影响因子：
9
通讯作者：
Seo HG
中科院分区：
文献类型：
--
作者：
Hwang JS;Lee WJ;Kang ES;Ham SA;Yoo T;Paek KS;Lim DS;Do JT;Seo HG
过氧化物酶体增殖物激活受体（PPARs）抑制脂多糖（LPS）引发的高迁移率基团1 （HMGB1）的释放，这是一种晚期促炎介质，但其潜在的分子机制尚不完全清楚。在这项研究中，我们证明了PPAR-δ和-γ对HMGB1释放的抑制与SIRT1的去乙酰化酶活性有关。配体激活的PPAR-δ和-γ抑制lps引发的HMGB1释放，同时SIRT1表达和启动子活性升高。这些效应在PPAR小干扰rna的存在下显著降低，表明PPAR-δ和-γ参与了HMGB1的释放和SIRT1的表达。此外，siRNA或化学物质对SIRT1表达和活性的调节也相应地影响PPARs对HMGB1释放的影响，提示SIRT1调节HMGB1释放的机制。此外，我们首次发现在LPS或p300/ cbp相关因子（PCAF）作用下乙酰化的HMGB1是SIRT1的有效底物，并且HMGB1的去乙酰化可阻断巨噬细胞中HMGB1的释放。最后，在SIRT1敲除小鼠的小鼠胚胎成纤维细胞中，HMGB1的乙酰化水平升高，而这种升高被SIRT1的异位表达完全逆转。这些结果表明，ppar介导的SIRT1上调调节了HMGB1乙酰化状态，而HMGB1乙酰化反过来又通过去乙酰化介导的HMGB1释放调节在细胞对炎症的反应中起关键作用。
Peroxisome proliferator-activated receptors (PPARs) inhibit lipopolysaccharide (LPS)-primed release of high mobility group box 1 (HMGB1), a late proinflammatory mediator, but the underlying molecular mechanism is not completely understood. In this study, we demonstrated that the inhibition of HMGB1 release by PPAR-δ and -γ is associated with the deacetylase activity of SIRT1. Ligand-activated PPAR-δ and -γ inhibited LPS-primed release of HMGB1, concomitant with elevation in SIRT1 expression and promoter activity. These effects were significantly reduced in the presence of small interfering (si)RNAs against PPAR, indicating that PPAR-δ and -γ are involved in both HMGB1 release and SIRT1 expression. In addition, modulation of SIRT1 expression and activity by siRNA or chemicals correspondingly influenced the effects of PPARs on HMGB1 release, suggesting a mechanism in which SIRT1 modulates HMGB1 release. Furthermore, we showed for the first time that HMGB1 acetylated in response to LPS or p300/CBP-associated factor (PCAF) is an effective substrate for SIRT1, and that deacetylation of HMGB1 is responsible for blockade of HMGB1 release in macrophages. Finally, acetylation of HMGB1 was elevated in mouse embryonic fibroblasts from SIRT1-knockout mice, whereas this increase was completely reversed by ectopic expression of SIRT1. These results indicate that PPAR-mediated upregulation of SIRT1 modulates the status of HMGB1 acetylation, which, in turn, has a critical role in the cellular response to inflammation through deacetylation-mediated regulation of HMGB1 release.