The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis

• Published in: Gut Vol. 67; no. 9; pp. 1704 - 1715
• Main Authors: Xiang, Dai-Min, Sun, Wen, Ning, Bei-Fang, Zhou, Teng-Fei, Li, Xiao-Feng, Zhong, Wei, Cheng, Zhuo, Xia, Ming-Yang, Wang, Xue, Deng, Xing, Wang, Wei, Li, Heng-Yu, Cui, Xiu-Liang, Li, Shi-Chao, Wu, Bin, Xie, Wei-Fen, Wang, Hong-Yang, Ding, Jin
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.09.2018
• Subjects: Actin; Animals; Apoptosis; Basic-Leucine Zipper Transcription Factors - metabolism; Bile; Biomarkers - metabolism; Cancer therapies; Cell activation; Clinical medicine; Cytokine Receptor gp130 - metabolism; Cytokines; Extracellular matrix; Fibrosis; Hepatic Stellate Cells - metabolism; Hepatocytes; Hepatology; Humans; Interleukin 6; Interleukin-6 - metabolism; Kinases; Leukemia; Liver; Liver cancer; Liver Cirrhosis - diagnosis; Liver Cirrhosis - metabolism; Liver Cirrhosis - prevention & control; Mice; Mice, Mutant Strains; Parenchyma; Patients; Phosphorylation; Predictive Value of Tests; Proteins; Rodents; Sensitivity and Specificity; Signal Transduction; Smooth muscle; Stat3 protein; STAT3 Transcription Factor - metabolism; Stellate cells; Transcription; Transcription factors; Up-Regulation; Wound healing; Hepatic stellate cell; Liver fibrosis; Hepatic leukemia factor; IL-6; STAT3
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2016-313392

Background and aimsLiver 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.MethodsThe 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.ResultsExpression 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.ConclusionsIn 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.