The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Nelson Institute of Environmental Medicine, New York University School of Medicine, New York, USA.
Gut. 2018 Sep;67(9):1704-1715. doi: 10.1136/gutjnl-2016-313392. Epub 2017 Jul 28.
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.
The fibrotic specimens of patients and HLF (hepatic leukemia factor) 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.
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 HLF 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.
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.
肝纤维化是一种创伤愈合反应，通过用疤痕组织代替功能实质来破坏肝脏结构和功能。最近的进展提高了我们对这一瘢痕形成过程的认识，但肝纤维化的确切机制还远未清楚。
使用患者的纤维化标本和 HLF（肝白血病因子）小鼠来评估 HLF 在肝纤维化中的表达和作用。使用原代小鼠肝星状细胞（HSCs）和人 HSC 系 Lx2 来研究 HLF 对 HSC 激活的影响及其潜在机制。
在患者的纤维化肝脏中检测到 HLF 的表达，但在健康个体的肝脏中不存在。有趣的是，HLF 表达局限于活化的 HSCs，而不是肝脏中的其他细胞类型。HLF 的缺失会损害原代 HSC 的激活，并减轻 HLF 小鼠的肝纤维化。一致地，异位 HLF 表达显著促进了人 HSCs 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，并增强了信号转导子和转录激活子 3（STAT3）的磷酸化，从而促进 HSC 的激活。巧合的是，IL-6/STAT3 信号在 HSCs 中反过来激活了 HLF 的表达，从而在 HSC 激活中完成了一个正反馈调节回路。此外，在患者的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。
总之，我们描绘了 HLF/IL-6/STAT3 调节回路在肝纤维化中的作用模式，并提出 HLF 是活化 HSCs 的一种新的生物标志物，也是抗纤维化治疗的潜在靶点。
