Low‐molecular‐weight fibroblast growth factor 2 attenuates hepatic fibrosis by epigenetic down‐regulation of Delta‐like1

• Published in: Hepatology (Baltimore, Md.) Vol. 61; no. 5; pp. 1708 - 1720
• Main Authors: Pan, Ruo‐Lang, Xiang, Li‐Xin, Wang, Ping, Liu, Xiao‐Yuan, Nie, Li, Huang, Wendong, Shao, Jian‐Zhong
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2015
• Subjects: Animals; Down-Regulation - drug effects; Epigenesis, Genetic - drug effects; Epigenetics; Fibroblast Growth Factor 2 - pharmacology; Fibroblast Growth Factor 2 - physiology; Fibroblast Growth Factor 2 - therapeutic use; Hepatology; Intercellular Signaling Peptides and Proteins - physiology; Kinases; Liver cirrhosis; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver diseases; Mice; Mice, Inbred C57BL; Molecular Weight; Rodents
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.27649

Liver fibrosis, a major cause of end‐stage liver diseases, is closely regulated by multiple growth factors and cytokines. The correlation of fibroblast growth factor 2 (FGF2) with chronic liver injury has been reported, but the exact functions of different FGF2 isoforms in liver fibrogenesis remain unclear. Here, we report on the differential expression patterns and functions of low‐ and high‐molecular‐weight FGF2 (namely, FGF2lmw and FGF2hmw, respectively) in hepatic fibrogenesis using a CCl4‐induced mouse liver fibrosis model. FGF2hmw displayed a robust increase in CCl4‐induced hepatic fibrosis and promoted fibrogenesis. In contrast, endogenous FGF2lmw exhibited a slight increase in hepatic fibrosis and suppressed this pathological progression. Moreover, exogenous administration of recombinant FGF2lmw potently ameliorated CCl4‐induced liver fibrosis. Mechanistically, we showed that FGF2lmw treatment attenuated hepatic stellate cell activation and fibrosis by epigenetic down‐regulation of Delta‐like 1 expression through the p38 mitogen‐activated protein kinase pathway. Conclusion: FGF2lmw and FGF2hmw have distinct roles in liver fibrogenesis. These findings demonstrate a potent antifibrotic effect of FGF2lmw administration, which may provide a novel approach to treat chronic liver diseases. (Hepatology 2015;61:1708–1720)