Modulation of collagen XVIII/endostatin expression in lobular and biliary rat liver fibrogenesis.
OBJECTIVE
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 alpha1(I) and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA expression in acute (single dose of CCl4) 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 CCl4 injection, C18 mRNA levels remained unchanged, while procollagen alpha1(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 alpha1(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 alpha1(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 anticancer therapy.
Jia
J D
JD
Department of Gastroenterology and Hepatology, University of Erlangen-Nuernberg, Erlangen, Germany.
Bauer
M
M
Sedlaczek
N
N
Herbst
H
H
Ruehl
M
M
Hahn
E G
EG
Riecken
E O
EO
Schuppan
D
D
D000818:Animals; D003094:Collagen / Q000235:genetics*; D043170:Collagen Type XVIII; D043169:Endostatins; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000235:genetics*; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics
D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D011347:Procollagen; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen