Modulation of collagen XVIII/endostatin expression in lobular and biliary rat liver fibrogenesis

Abstract

Background/Aims : The liver is the major source of collagen XVIII (C18), the precursor of the angiogenesis inhibitor endostatin. In human liver C18 is mainly expressed by hepatocytes. However, its quantitative and temporospatial expression patterns during liver fibrogenesis are unknown. Methods : We used RNA quantification and in situ hybridization combined with cell-specific markers to study C18 compared to procollagen α1(I) and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA expression in acute (single dose of CCl 4) and chronic (biliary) rat liver fibrogenesis. Results : C18 transcripts were only found in hepatocytes and bile duct epithelia of normal and fibrotic livers, and occasionally in arterial myocytes and hepatic stellate cells. 72 h after CCl 4 injection, C18 mRNA levels remained unchanged, while procollagen α1(I) mRNA was increased at 72 h and TIMP-1 mRNA peaked at 12 h ( P <0.05). In biliary fibrosis C18 mRNA levels increased 1.8-fold, contrasting with 20- and 4-fold elevated procollagen α1(I) and TIMP-1 transcript levels, respectively. Conclusions : Hepatocytes and bile duct epithelia are the predominant sources of C18 in normal and fibrotic rat liver. Contrary to procollagen α1(I) and TIMP-1, C18 expression remains constant in acute fibrogenesis and is upregulated in biliary fibrosis. Modulation of epithelial C18 expression and its processing to endostatin could allow a liver-specific anti-cancer therapy.