Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl4 (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl4-induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.

中文翻译：

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在急性和慢性肝病中与炎症相关的代谢基因网络抑制。

炎症已经被认为是恢复再生必不可少的。在这里，我们基于时间分辨的转录调节网络（TRN）分析了肝损伤发作和随后的再生过程中的顺序过程，以了解炎症，成熟器官功能和再生之间的关系。CCl4急性损伤后（2 h，8 h，1、2、4、6、8、16天）以及脂多糖（LPS，24 h）在小鼠肝脏中进行时间依赖性的全基因组表达和TRN分析并将其与衣霉素暴露（小鼠，6小时），肝细胞癌（HCC，小鼠）和人类慢性肝病（非酒精性脂肪肝，HBV感染和HCC）后的公开数据进行比较。时空调查区分小叶区域的信号和转录因子表达。急性CCl4中毒诱导炎症和应激信号丰富的基因簇的表达在2至24小时内达到峰值，伴随着成熟肝功能的降低，尤其是代谢基因的降低。代谢不仅在经历CCl4诱导的坏死的中枢肝细胞中减少，而且扩展到存活的门静脉肝细胞中。增殖和组织修复性TRN仅在后来出现，在48小时达到最大值。相同的上游调节因子（例如，RXR功能受到抑制）与炎症增加和代谢受到抑制有关。在急性LPS和衣霉素攻击后，慢性小鼠模型以及人类肝脏疾病中，伴随的炎症/新陈代谢TRN相似地发生。伴随发生代谢基因的下调以诱导炎症相关基因作为早期反应，并且似乎由人类和小鼠的急性和慢性肝病中的类似上游调节剂引发。在急性环境中，与增殖和恢复性再生有关的TRN仅在新陈代谢已被抑制时才达到峰值。