NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice.
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice.
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DOI：
10.1016/j.redox.2020.101841
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发表时间：
2021-04
期刊：
影响因子：
11.4
通讯作者：
Fabregat I
中科院分区：
文献类型：
--
作者：
Herranz-Itúrbide M;López-Luque J;Gonzalez-Sanchez E;Caballero-Díaz D;Crosas-Molist E;Martín-Mur B;Gut M;Esteve-Codina A;Jaquet V;Jiang JX;Török NJ;Fabregat I
肝脏是一个独特的器官，在急性/慢性损伤或部分肝切除后会表现出修复和再生反应，此时所有细胞类型都必须增殖以重建肝脏质量。NADPH氧化酶NOX4介导转化生长因子 -β（TGF -β）的作用，包括肝细胞的凋亡以及星状细胞向肌成纤维细胞的活化。本研究的目的是通过使用两种Nox4缺失的小鼠模型来分析NOX4在肝脏再生中的影响：1）Nox4全身性缺失（NOX4 - / -）和2）肝细胞特异性Nox4缺失（NOX4hepKO）。在2/3部分肝切除（PH）后分析肝脏再生情况。结果表明，与相应的野生型小鼠相比，NOX4 - / -和NOX4hepKO小鼠的肝脏与体重比恢复得更早，存活率也更高。在NOX4缺失的肝脏中，再生肝细胞脂肪堆积和实质组织结构恢复得更快。通过Ki67和磷酸化组蛋白3免疫组化分析，NOX4缺失小鼠的肝细胞增殖加速且增加，同时Myc表达更早且增加。从NOX4缺失小鼠分离的原代肝细胞显示出更高的增殖能力，并且对血清的反应中Myc和不同细胞周期蛋白的表达增加。通过RNA - seq进行的转录组分析显示，PH后NOX4 - / -小鼠有显著变化，并支持Myc在增殖相关基因调控节点中的相关作用。有趣的是，RNA - seq还揭示了与TGF -β途径激活相关基因表达的变化。事实上，在NOX4缺失小鼠中，活性TGF -β1水平、Smads的磷酸化以及其靶标p21的水平在24小时时较低。Nox4对于体内肝脏再生的终止似乎不是必需的，对于体外肝细胞对TGF -β1的生长抑制反应也不是必需的，这表明它作为改善肝脏再生的治疗靶点具有潜力，且无不良影响。
全身性或肝细胞特异性Nox4缺失加速小鼠肝脏再生。
观察到肝细胞增殖增加，同时Myc表达更高。
RNA - seq分析揭示了Myc在基因表达调控节点中的作用。
在体内观察到TGF -β1途径的转录和功能减弱。
在体外，Nox4缺失的肝细胞对TGF -β1保持生长抑制反应。
Liver is a unique organ in displaying a reparative and regenerative response after acute/chronic damage or partial hepatectomy, when all the cell types must proliferate to re-establish the liver mass. The NADPH oxidase NOX4 mediates Transforming Growth Factor-beta (TGF-β) actions, including apoptosis in hepatocytes and activation of stellate cells to myofibroblasts. Aim of this work was to analyze the impact of NOX4 in liver regeneration by using two mouse models where Nox4 was deleted: 1) general deletion of Nox4 (NOX4−/−) and 2) hepatocyte-specific deletion of Nox4 (NOX4hepKO). Liver regeneration was analyzed after 2/3 partial hepatectomy (PH). Results indicated an earlier recovery of the liver-to-body weight ratio in both NOX4−/− and NOX4hepKO mice and an increased survival, when compared to corresponding WT mice. The regenerative hepatocellular fat accumulation and the parenchyma organization recovered faster in NOX4 deleted livers. Hepatocyte proliferation, analyzed by Ki67 and phospho-Histone3 immunohistochemistry, was accelerated and increased in NOX4 deleted mice, coincident with an earlier and increased Myc expression. Primary hepatocytes isolated from NOX4 deleted mice showed higher proliferative capacity and increased expression of Myc and different cyclins in response to serum. Transcriptomic analysis through RNA-seq revealed significant changes after PH in NOX4−/− mice and support a relevant role for Myc in a node of regulation of proliferation-related genes. Interestingly, RNA-seq also revealed changes in the expression of genes related to activation of the TGF-β pathway. In fact, levels of active TGF-β1, phosphorylation of Smads and levels of its target p21 were lower at 24 h in NOX4 deleted mice. Nox4 did not appear to be essential for the termination of liver regeneration in vivo, neither for the in vitro hepatocyte response to TGF-β1 in terms of growth inhibition, which suggest its potential as therapeutic target to improve liver regeneration, without adverse effects. General or hepatocyte-specific Nox4 deletion accelerates mice liver regeneration. Increased hepatocyte proliferation is observed, coincident with higher Myc expression. RNA-seq analysis reveals a role for Myc in a node of regulation of gene expression. Transcriptional and functional attenuation of the TGF-β1 pathway is observed in vivo. In vitro, Nox4 deleted hepatocytes maintain the growth inhibitory response to TGF-β1.
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影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
DOI：
10.1007/978-1-4939-9424-3_2
发表时间：
2019-01-01
期刊：
NADPH OXIDASES: METHODS AND PROTOCOLS
影响因子：
--
作者：
Buvelot, Helene;Jaquet, Vincent;Krause, Karl-Heinz
通讯作者：
Krause, Karl-Heinz
影响因子：
--
作者：
Edmunds LR;Otero PA;Sharma L;D'Souza S;Dolezal JM;David S;Lu J;Lamm L;Basantani M;Zhang P;Sipula IJ;Li L;Zeng X;Ding Y;Ding F;Beck ME;Vockley J;Monga SP;Kershaw EE;O'Doherty RM;Kratz LE;Yates NA;Goetzman EP;Scott D;Duncan AW;Prochownik EV
通讯作者：
Prochownik EV
影响因子：
5.6
作者：
Herrera, B;Alvarez, AM;Fernández, M
通讯作者：
Fernández, M
影响因子：
24.5
作者：
Dropmann, Anne;Dooley, Steven;Meindl-Beinker, Nadja M.
通讯作者：
Meindl-Beinker, Nadja M.