Inactivation of Sirt1 in mouse livers protects against endotoxemic liver injury by acetylating and activating NF-κB.
Inactivation of Sirt1 in mouse livers protects against endotoxemic liver injury by acetylating and activating NF-κB.
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小鼠肝脏中 Sirt1 的失活可通过乙酰化和激活 NF-kappaB 来防止内毒素血症性肝损伤。
DOI：
10.1038/cddis.2016.270
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发表时间：
2016-10-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
Sirtuin 1（Sirt 1）是一种调节肝脏中许多细胞过程的脱乙酰酶，到目前为止，它在内毒素性肝损伤中的作用尚不清楚。因此，我们在小鼠肝细胞中有条件地表达Sirt 1，以确定其在d-半乳糖胺（GalN）/脂多糖（LPS）诱导的肝损伤中的作用，这是一个成熟的模拟脓毒性肝损伤和暴发性肝炎的实验模型。Sirt 1的去除显示出对GalN/LPS诱导的肝损伤的显著保护，这是增强的NF-κB应答的结果，因为RelA/p65的敲除否定了Sirt 1敲除的保护作用。从机制上讲，NF-κB p65在肿瘤坏死因子-α（TNF-α）激发的白蛋白-Cre+（AlbCre+）肝细胞中维持在高乙酰化的DNA结合活性状态。用重组乙酰化p65表达构建体转染肝细胞复制了Sirt 1敲除所提供的保护。用重组野生型Sirt 1构建体转染AlbCre+肝细胞，而不是去乙酰化酶缺陷型，损害NF-κB活化，并使肝细胞对TNF-α诱导的细胞凋亡重新敏感。综上所述，我们的研究结果表明，Sirt 1去乙酰化p65和妥协NF-κB活性在肝细胞面临LPS/TNF-α刺激，导致增加的易感性内毒素损伤。这些发现确定了一种可能的蛋白效应物，在炎症环境下操纵肝脏NF-κB信号通路，并确定了一种可行的方法来增加肝细胞对内毒素/TNF-α毒性的抵抗力。
Sirtuin 1 (Sirt1) is a deacetylase that regulates many cellular processes in the liver, and so far its role in endotoxemic liver injury is elusive. So we conditionally inactivate Sirt1 in murine hepatocytes to determine its role in d-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver damage, which is a well-established experimental model mimicking septic liver injury and fulminant hepatitis. Ablation of Sirt1 shows remarkable protection against GalN/LPS-induced liver injury, which is a result of enhanced NF-κB response because knockdown of RelA/p65 negates the protective effect of Sirt1 knockout. Mechanistically, NF-κB p65 is maintained in a hyperacetylated, DNA-binding competent state in tumor necrosis factor-α (TNF-α)-challenged albumin-Cre+ (AlbCre+) hepatocytes. Transfection of hepatocytes with a recombinant acetylated p65 expression construct replicates the protection afforded by Sirt1 knockout. Transfection of AlbCre+ hepatocytes with a recombinant wild-type Sirt1 construct, rather than a deacetylase-defective one, compromises NF-κB activation and resensitizes hepatocytes to TNF-α-induced apoptosis. Taken together, our results demonstrate that Sirt1 deacetylates p65 and compromises NF-κB activity in hepatocytes when confronted with LPS/TNF-α stimulation, leading to increased susceptibility to endotoxemic injury. These findings identify a possible protein effector to maneuver the hepatic NF-κB signaling pathway under inflammatory circumstances and a feasible way to increase hepatocellular resistance to endotoxin/TNF-α toxicity.
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