Accelerated Partial Hepatectomy-Induced Liver Cell Proliferation Is Associated with Liver Injury in Nur77 Knockout Mice
Accelerated Partial Hepatectomy-Induced Liver Cell Proliferation Is Associated with Liver Injury in Nur77 Knockout Mice
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DOI：
10.1016/j.ajpath.2014.08.002
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发表时间：
2014-12-01
影响因子：
6
通讯作者：
Wan, Yu-Jui Yvonne
中科院分区：
文献类型：
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作者：
Hu, Ying;Zhan, Qi;Wan, Yu-Jui Yvonne
Nur77 由 Nr4a1（别名 Nur77）编码，在细胞死亡、存活和炎症中发挥着重要作用。为了研究 Nur77 在肝再生中的作用，对野生型 (WT) 和 Nur77 敲除 (KO) 小鼠进行标准的三分之二部分肝切除术 (PH)。 WT 肝脏中 PH 后 1 小时，Nur77 mRNA 和蛋白质水平显着诱导，与 ERK1/2 激活同时发生。令人惊讶的是，在 PH 后 24、48 和 72 小时，Nur77 KO 小鼠表现出比 WT 小鼠更高的肝脏重量比。 Nur77 KO 肝脏在 24 小时内表现出 Ki-67 阳性肝细胞的增加，并早期诱导细胞周期基因。尽管加速了再生，Nur77 KO 肝脏却矛盾地引起了坏死、肝细胞凋亡、血清丙氨酸转氨酶活性升高和库普弗细胞积聚。微阵列分析显示调节炎症、细胞增殖和凋亡的基因上调，但葡萄糖和脂质稳态基因下调（由于 Nur77 缺陷）。与WT相比，促炎细胞因子IL-6、IL-12、IL-23和CCL2的水平升高，抗炎细胞因子IL-10的水平降低。 Nur77 KO 肝脏中激活的 NF-B-kappa 和 STAT3 以及靶基因 Myc 和 Bcl2l1 的 mRNA 水平升高。总体而言，Nur77 通过调节细胞因子介导的炎症、细胞凋亡和能量动员过程，对于调节肝脏再生的早期信号传导至关重要。在 Nur77 KO 小鼠中观察到的肝再生加速可能是由于损伤引起的代偿效应。
Nur77, encoded by Nr4a1 (alias Nur77), plays rotes in cell death, survival, and inflammation. To study the role of Nur77 in liver regeneration, wild-type (WT) and Nur77 knockout (KO) mice were subjected to standard two-thirds partial hepatectomy (PH). Nur77 mRNA and protein levels were markedly induced at 1 hour after PH in WT livers, coinciding with ERK1/2 activation. Surprisingly, Nur77 KO mice exhibited a higher liver-to-body weight ratio than WT mice at 24, 48, and 72 hours after PH. Nur77 KO livers exhibited increase in Ki-67-positive hepatocytes at 24 hours, with early induction of cell-cycle genes. Despite accelerated regeneration, Nur77 KO livers paradoxically incurred necrosis, hepatocyte apoptosis, elevated serum aLanine aminotransferase activity, and Kupffer cell accumulation. Microarray analysis revealed upregulation of genes modulating inflammation, cell proliferation, and apoptosis but down-regulation (due to Nur77 deficiency) of glucose and lipid homeostasis genes. Levels of proinflammatory cytokines IL-6, IL-12, IL-23, and CCL2 were increased and levels of anti-inflammatory IL-10 were decreased, compared with WT. Activated NF-B-kappa and STAT3 and mRNA levels of target genes Myc and Bcl2l1 were elevated in Nur77 KO livers. Overall, Nur77 appears essential for regulating early signaling of Liver regeneration by modulating cytokine-mediated inflammatory, apoptotic, and energy mobilization processes. The accelerated liver regeneration observed in Nur77 KO mice is Likely due to a compensatory effect caused by injury.