Hepatocyte-specific IKKγ/NEMO expression determines the degree of liver injury
Hepatocyte-specific IKKγ/NEMO expression determines the degree of liver injury
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DOI：
10.1053/j.gastro.2007.03.045
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发表时间：
2007-06-01
期刊：
影响因子：
29.4
通讯作者：
Trautwein, Christian
中科院分区：
文献类型：
--
作者：
Beraza, Naiara;Ludde, Tom;Trautwein, Christian
背景和目标：NEMO是I κ B激酶（IKK）复合物的调节亚基，参与控制核因子κ B（NF-κ B）活化。NEMO基因敲除小鼠在胚胎发育过程中由于大量肝细胞凋亡而死亡。在这里，我们研究了NEMO依赖性信号在急性肝损伤中的作用。研究方法：我们使用具有Cre重组酶的loxP系统在白蛋白启动子（NEMO Delta LPC）的控制下产生条件性肝细胞特异性NEMO敲除小鼠。在这些小鼠中，我们研究了肿瘤坏死因子（TNF）和缺血/再灌注依赖性肝细胞损伤的机制。结果如下：在成年NEMO Delta LPC动物中，NEMO在肝细胞中特异性缺失，与野生型（NEMOf/f）小鼠相比，未发现存活、生长和生育力差异。NEMO Delta LPC小鼠的TNF刺激导致高血清转氨酶水平和大量肝细胞凋亡，这与缺乏I κ B α降解、抑制NF-κ B活化和靶基因转录相关。此外，在NEMO Delta LPC小鼠中，缺血/再灌注导致更高的非实质细胞依赖性氧化应激诱导和更强的炎症。这导致大量的肝细胞凋亡和动物死亡，而NEMOf/f小鼠存活，肝损伤明显较少，主要表现为坏死细胞死亡。因此，与肝细胞特异性IKK 2（-/-）小鼠中的衰减相反，肝细胞中NF-κ B活化的完全抑制决定了缺血/再灌注损伤期间肝细胞损伤的类型，并且与不良预后相关。结论：我们的研究结果表明，理解肝损伤过程中NF-κ B调节的微调对于开发新的治疗策略至关重要。
Background & Aims: NEMO is the regulatory subunit of the I kappa B kinase (IKK) complex and is involved in controlling nuclear factor kappa B (NF-kappa B) activation. NEMO knockout mice die during embryogenesis due to massive hepatocyte apoptosis. Here we investigated the role of NEMO-dependent signaling in hepatocytes during acute liver injury. Methods: We generated conditional hepatocyte-specific NEMO knockout mice using the loxP system with the Cre recombinase under the control of the albumin promoter (NEMO Delta LPC). In these mice, we studied mechanisms of tumor necrosis factor (TNF)- and ischemia/reperfusion-dependent liver cell damage. Results: In adult NEMO Delta LPC animals, NEMO is specifically deleted in hepatocytes and no differences in survival, growth, and fertility were found when compared with wild-type (NEMOf/f) mice. TNF stimulation of NEMO Delta LPC mice resulted in high serum transaminase levels and massive hepatocyte apoptosis, which were associated with lack of I kappa B alpha degradation, inhibition of NF-kappa B activation, and target gene transcription. Additionally, ischemia/reperfasion resulted in higher non-parenchymal cell-dependent induction of oxidative stress and stronger inflammation in NEMO Delta LPC mice. This led to massive hepatocyte apoptosis and death of the animals, while NEMOf/f mice survived with significantly lesser liver damage, showing mainly necrotic cell death. Thus, complete inhibition of NF-kappa B activation in hepatocytes, in contrast to attenuation in hepatocyte-specific IKK2(-/-) mice, determines the type of liver cell damage during ischemia/reperfusion injury and is associated with a poor prognosis. Conclusions: Our results show that understanding of the fine tuning of NF-kappa B modulation during liver injury is essential to develop new therapeutic strategies.