The effects of fibroblast growth factor signaling on liver homeostasis and regeneration

• Main Authors: Su-Mei Tsai, 蔡夙美
• Other Authors: Wen-Pin Wang
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/92664054154557648423

博士 === 慈濟大學 === 醫學科學研究所 === 100 === In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. However, the function of Fgf signaling in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. In the first part of this study, we studied the function of this signaling pathway in zebrafish liver. The expression of fgf receptors (fgfrs) in the liver of zebrafish was analyzed. We created a transgenic fish expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). A small liver size with defected medial expansion of developing livers was observed in lf:dnfr larvae. Degeneration of hepatocytes was observed in the liver of adult lf:dnfr fish and further examination revealed the development of hepatic steatosis and cholestasis. We unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Notably, we detected the formation of cholangiocarcinoma in lf:dnfr fish, with the incidence increasing with age. We concluded that in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling and disruption of this signaling might indirectly cause tumor formation. Besides regulating metabolism, FGF signaling also promotes hepatocyte proliferation and helps detoxify hepatotoxin during liver regeneration. Liver regeneration after partial hepatectomy (PH) is impaired in transgenic mice expressing dnFGFR2b in hepatocytes. Although FGF7, a ligand specifically bound to FGFR2b, is expressed by activated hepatic stellate cells (HSCs) in fibrotic livers, the expressions and functions of FGF7 after PH remain unexplored. The second part of this study sought to examine the potential role of FGF7 signaling in this process. Importantly, we found increased FGF7 expression in activated HSCs after PH. Its receptor, FGFR2b, was also increased in hepatocytes during liver regeneration. In vitro study using primary hepatocytes with FGF7 recombinant protein and in vivo study using hydrodynamics to express FGF7 in the liver both revealed that FGF7 protein activated ERK1/2 and promoted proliferation of hepatocytes after PH, indicating an unidentified role of activated HSC-expressed FGF7 during liver regeneration.