Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease
Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease
复制标题
DOI：
10.1007/s00204-019-02630-3
复制
发表时间：
2020-01-01
影响因子：
6.1
通讯作者：
Godoy, Patricio
中科院分区：
文献类型：
--
作者：
Campos, Gisela;Schmidt-Heck, Wolfgang;Godoy, Patricio
炎症已被认为对于恢复性再生至关重要。在这里，我们基于时间分辨转录调控网络（TRN）分析了肝损伤发生和随后再生期间的顺序过程，以了解炎症、成熟器官功能和再生之间的关系。在 CCl4（2 小时、8 小时、1、2、4、6、8、16 天）以及脂多糖（LPS，24 小时）急性损伤后，对小鼠肝脏进行时间依赖性全基因组表达和 TRN 分析，并与衣霉素暴露（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，乙型肝炎病毒感染和肝癌）。时空研究区分了信号传导和转录因子表达的小叶区域。急性 CCl4 中毒诱导富含炎症和应激信号的基因簇表达，并在 2 至 24 小时内达到峰值，并伴有成熟肝功能的下降，特别是代谢基因的下降。代谢不仅在经历 CCl4 诱导坏死的中央周围肝细胞中下降，而且延伸到幸存的门静脉周围肝细胞。增殖和组织恢复 TRN 仅在稍后才发生，并在 48 小时时达到最大值。相同的上游调节因子（例如抑制 RXR 功能）与炎症增加和代谢抑制有关。在慢性小鼠模型和人类肝脏疾病中，急性 LPS 和衣霉素激发后，伴随的炎症/代谢 TRN 也发生类似的情况。代谢基因的下调同时发生，以诱导炎症相关基因作为早期反应，并且似乎是由人类和小鼠急性和慢性肝病中类似的上游调节因子启动的。在急性情况下，与 TRN 相关的增殖和恢复性再生仅在新陈代谢已受到抑制后才达到峰值。
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.