NF-κB Essential Modifier Is Required for Hepatocyte Proliferation and the Oval Cell Reaction After Partial Hepatectomy in Mice
NF-κB Essential Modifier Is Required for Hepatocyte Proliferation and the Oval Cell Reaction After Partial Hepatectomy in Mice
复制标题
DOI：
10.1053/j.gastro.2012.08.030
复制
发表时间：
2012-12-01
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：
Malato, Yann;Ehedego, Haksier;Trautwein, Christian
背景与目的：转录因子核因子κ B（NF-κ B）由I κ B激酶复合物激活。该复合物的调节亚基NF-κ B必需修饰物（NEMO或IKBKG）是肿瘤抑制因子。肝细胞特异性NEMO缺失诱导慢性肝脏炎症，导致细胞凋亡、氧化应激、非酒精性脂肪性肝炎的发展和肝癌发生。方法：我们用肝细胞特异性破坏NEMO（Nemo（Delta hepa））对小鼠进行部分肝切除。一些小鼠喂食含有抗氧化剂丁基羟基茴香醚（BHA）的饮食，另一些小鼠每天腹腔注射氧化剂苯乙基异硫氰酸酯（PEITC）。研究结果：Nemo（Delta hepa）小鼠在部分肝切除术后肝再生受损，死亡率为50%，表明NEMO是再生反应所必需的。小鼠的肝细胞具有强烈的氧化应激反应;这些细胞下调了NF-κ B依赖的抗氧化反应，并降低了修复DNA双链断裂的蛋白质水平。然而，肝细胞增殖的损害是由Nemo（Delta hepa）小鼠卵圆细胞的反应补偿的。卵圆细胞表达低水平的白蛋白，从而表达正常水平的NEMO。用表达NEMO的卵圆细胞重建肝脏可逆转Nemo（Delta hepa）小鼠的肝损伤。有趣的是，这些小鼠在部分肝切除术后6个月仍然发生肝细胞癌，而喂食BHA饮食的Nemo（Delta hepa）小鼠则免受致癌作用的影响。结论：在小鼠肝脏中，NEMO的表达和NF-κ B B的活化是肝细胞增殖和肝再生的必要条件。这些机制需要控制氧化应激和DNA完整性。
BACKGROUND & AIMS: The transcription factor nuclear factor kappa B (NF-kappa B) is activated by the I kappa B kinase complex. The regulatory subunit of this complex, NF-kappa B essential modifier (NEMO or IKBKG), is a tumor suppressor. Hepatocyte-specific deletion of NEMO induces chronic liver inflammation that leads to apoptosis, oxidative stress, development of nonalcoholic steatohepatitis, and hepatocarcinogenesis. METHODS: We performed partial hepatectomies in mice with hepatocyte-specific disruption of NEMO (Nemo(Delta hepa)). Some mice were fed a diet that contained the antioxidant butylated hydroxyanisole (BHA), and others were given daily intraperitoneal injections of the oxidant phenetyl isothiocyanate (PEITC). RESULTS: Nemo(Delta hepa) mice had impaired liver regeneration after partial hepatectomy and 50% mortality, indicating that NEMO is required for the regenerative response. Liver cells of the mice had a strong oxidative stress response; these cells down-regulated the NF-kappa B-dependent antioxidant response and reduced levels of proteins that repair DNA double-strand breaks. However, the impairments to hepatocyte proliferation were compensated by a response of oval cells in Nemo(Delta hepa) mice. Oval cells expressed low levels of albumin and thereby expressed normal levels of NEMO. Repopulation of the liver with oval cells that expressed NEMO reversed liver damage in Nemo(Delta hepa) mice. Interestingly, these mice still developed hepatocellular carcinomas 6 months after partial hepatectomy, whereas Nemo(Delta hepa) mice fed the BHA diet were protected from carcinogenesis. CONCLUSIONS: In livers of mice, expression of NEMO and activation of NF-kappa B are required for hepatocyte proliferation and liver regeneration. These mechanisms require control of oxidative stress and DNA integrity.