Pierre Ketsia B, Jones Christopher M, Pierce Janene M, Nicoud Ian B, Earl T Mark, Chari Ravi S
Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4753, USA.
J Surg Res. 2009 Jun 15;154(2):226-33. doi: 10.1016/j.jss.2008.07.023. Epub 2008 Aug 27.
Liver regeneration following partial hepatectomy requires the orchestration of highly regulated molecular pathways; a change in the abundance or activity of a specific gene product has the potential to adversely affect this process. The nuclear factor of activated T-cells (NFAT) transcription factors represent a family of gene transcription signaling intermediates that translate receptor-dependent signaling events into specific transcriptional responses using the Ras/Raf pathway.
Eight-week old NFAT4 knockout (KO) mice and their wild type counterparts (Balb-c) underwent two-thirds partial hepatectomy. The animals were sacrificed and their livers were harvested at specific time points during regeneration. Recovery of liver mass was measured for each time point. PCR analysis was used to analyze expression levels of the immediate early genes c-fos, c-jun and c-myc as well as downstream effectors of NFAT4 including FGF-18 and BMP-4.
Hepatocyte proliferation and thus liver regeneration following hepatectomy was suppressed in NFAT4 knockout (KO) mice. Statistical significance was reached at 1 h, 7 d, and 10 d (P < 0.05) with a 22% median reduction in regeneration of liver mass in the NFAT4 KO mice by 10 d, at which time liver regeneration should be complete in mice. The immediate early gene c-fos was elevated in NFAT4 KO mice during early regeneration with a median value at 1 h and 1 d of 1.60E-08 and 1.09E-08 versus 6.10E-09 and 1.55E-09 in the Balb-c mice. C-jun, in contrast, was elevated during late regeneration in the NFAT4 KO mice (3.40E-09 and 5.67E-09 at 7 and 10 d, respectively) in comparison with the Balb-c mice (7.76E-10 and 1.24E-09, respectively.). NFAT2 was also up-regulated in the NFAT4 KO mice; however, no changes were detected in its downstream effectors, CCR1 and CCL3.
We demonstrated that NFAT4 deficiency impairs hepatic regeneration in a murine model proving that NFAT4 plays an important yet unclear role in liver regeneration; its absence may be compensated by c-fos, c-jun, and NFAT2 expression changes.
部分肝切除术后的肝脏再生需要高度调控的分子途径协同作用；特定基因产物丰度或活性的改变有可能对这一过程产生不利影响。活化T细胞核因子（NFAT）转录因子代表一类基因转录信号中间体，其利用Ras/Raf途径将受体依赖性信号事件转化为特定的转录反应。
8周龄的NFAT4基因敲除（KO）小鼠及其野生型对照（Balb-c小鼠）接受了三分之二部分肝切除术。在再生过程中的特定时间点处死动物并采集肝脏。测量每个时间点肝脏重量的恢复情况。采用PCR分析来检测即刻早期基因c-fos、c-jun和c-myc的表达水平以及NFAT4的下游效应分子，包括FGF-18和BMP-4。
NFAT4基因敲除（KO）小鼠肝切除术后的肝细胞增殖以及肝脏再生受到抑制。在1小时、7天和10天时差异具有统计学意义（P < 0.05），到10天时NFAT4基因敲除小鼠肝脏重量再生的中位数降低了22%，而此时正常小鼠的肝脏再生应已完成。在早期再生过程中，NFAT4基因敲除小鼠的即刻早期基因c-fos升高，在1小时和1天时的中位数分别为1.60E-08和1.09E-08，而Balb-c小鼠分别为6.10E-09和1.55E-09。相比之下，NFAT4基因敲除小鼠在晚期再生过程中c-jun升高（在7天和10天时分别为3.40E-09和5.67E-09），而Balb-c小鼠分别为7.76E-10和1.24E-09。NFAT2在NFAT4基因敲除小鼠中也上调；然而，其下游效应分子CCR1和CCL3未检测到变化。
我们证明了NFAT4缺陷会损害小鼠模型中的肝脏再生，这表明NFAT4在肝脏再生中起重要但尚不清楚的作用；其缺失可能通过c-fos、c-jun和NFAT2表达的变化得到补偿。
