Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1.
OBJECTIVE
Silymarin reduces hepatic collagen accumulation by 35% in rats with secondary biliary cirrhosis. The aim of the present study was to explore its antifibrotic mechanism.


METHODS
Thirty female adult Wistar rats were allocated to (1) bile duct occlusion, (2) bile duct occlusion and oral silymarin at 50 mg/kg per day, and (3) sham operation and oral silymarin at 50 mg/kg per day. Steady-state mRNA levels for procollagen alpha1(I), tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth factor (TGF) beta1 were determined by multi-probe ribonuclease protection assay.


RESULTS
After 6 weeks of bile duct occlusion, liver collagen content was increased 12-fold, when compared with the sham-operated controls. These animals displayed 17-, 6.5- and 16-fold higher transcript levels for procollagen alpha1(I), TIMP-1 and TGFbeta1 (P < 0.01). Silymarin downregulated elevated procollagen alpha1(I), TIMP-1 and TGFbeta1 mRNA levels by 40-60% (P < 0.01). These lowered hepatic profibrogenic transcript levels correlated with decreased serum levels of the aminoterminal propeptide of procollagen type III.


CONCLUSIONS
Silymarin suppresses expression of profibrogenic procollagen alpha1(I) and TIMP-1 most likely via downregulation of TGFbeta1 mRNA in rats with biliary fibrosis. The serum procollagen type III propeptide level mirrors profibrogenic mRNA expression in the liver.
Jia
J D
JD
Department of Gastroenterology and Hepatology, Friedrich-Alexander University, Erlangen-Nuernberg, Erlangen, Germany.
Bauer
M
M
Cho
J J
JJ
Ruehl
M
M
Milani
S
S
Boigk
G
G
Riecken
E O
EO
Schuppan
D
D
D000818:Animals; D003094:Collagen / Q000032:analysis; D017364:Collagenases / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D010446:Peptide Fragments / Q000032:analysis; D011347:Procollagen / Q000032:analysis / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D012838:Silymarin / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*
D010446:Peptide Fragments; D011347:Procollagen; D012838:Silymarin; D019715:Tissue Inhibitor of Metalloproteinase-1; C041876:procollagen Type III-N-terminal peptide; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D019278:Matrix Metalloproteinase 3