Hu Ying, Zhan Qi, Liu Hui-Xin, Chau Thinh, Li Yuyuan, Wan Yu-Jui
Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California.
Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Guangzhou Digestive Disease Center, Guangzhou, China.
Am J Pathol. 2014 Dec;184(12):3272-83. doi: 10.1016/j.ajpath.2014.08.002. Epub 2014 Oct 7.
Nur77, encoded by Nr4a1 (alias Nur77), plays roles 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 up-regulation 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-κB 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.
由Nr4a1（别名Nur77）编码的Nur77在细胞死亡、存活和炎症过程中发挥作用。为了研究Nur77在肝脏再生中的作用，对野生型（WT）和Nur77基因敲除（KO）小鼠进行标准的三分之二部分肝切除术（PH）。在野生型肝脏中，PH术后1小时Nur77 mRNA和蛋白水平显著诱导，与ERK1/2激活同时发生。令人惊讶的是，在PH术后24、48和72小时，Nur77基因敲除小鼠的肝体重比高于野生型小鼠。Nur77基因敲除肝脏在24小时时Ki-67阳性肝细胞增加，细胞周期基因早期诱导。尽管再生加速，但Nur77基因敲除肝脏却出现坏死、肝细胞凋亡、血清丙氨酸转氨酶活性升高和库普弗细胞聚集。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缺乏）。与野生型相比，促炎细胞因子IL-6、IL-12、IL-23和CCL2水平升高，抗炎性IL-10水平降低。在Nur77基因敲除肝脏中，活化的NF-κB和STAT3以及靶基因Myc和Bcl2l1的mRNA水平升高。总体而言，Nur77似乎通过调节细胞因子介导的炎症、凋亡和能量动员过程，对调节肝脏再生的早期信号至关重要。在Nur77基因敲除小鼠中观察到的加速肝脏再生可能是由损伤引起的代偿效应所致。
