Background and aims Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear. Methods The fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism. Results Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis. Conclusions In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.

中文翻译：

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HLF/IL-6/STAT3前馈电路驱动肝星状细胞活化促进肝纤维化

背景和目的 肝纤维化是一种伤口愈合反应，通过用疤痕组织替代功能性实质来破坏肝脏结构和功能。最近的进展提高了我们对这种瘢痕形成过程的认识，但肝纤维化的详细机制尚不清楚。方法采用患者和HLF（肝白血病因子）PB/PB小鼠的纤维化标本评估HLF在肝纤维化中的表达和作用。原代鼠肝星状细胞 (HSC) 和人 HSC 系 Lx2 用于研究 HLF 对 HSC 活化的影响及其潜在机制。结果患者的纤维化肝脏中检测到HLF的表达，而健康人的肝脏中不存在HLF的表达。有趣的是，HLF 表达仅限于活化的 HSC，而不是肝脏中的其他细胞类型。HLF 的缺失损害了 HLFPB/PB 小鼠的原发性 HSC 活化并减弱了肝纤维化。一致地，异位 HLF 表达显着促进了人类 HSC 的激活。机制研究表明，上调的 HLF 转录增强了白细胞介素 6 (IL-6) 的表达并增强了信号转导和转录激活因子 3 (STAT3) 的磷酸化，从而促进了 HSC 的活化。巧合的是，IL-6/STAT3 信号转而激活 HSC 中的 HLF 表达，从而完成了 HSC 激活中的前馈调节回路。此外，在患者纤维化肝脏中观察到 HLF 表达与 α-平滑肌肌动蛋白、IL-6 和 p-STAT3 水平之间的相关性，支持 HLF/IL-6/STAT3 级联在肝纤维化中的作用。结论 总的来说，