Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1.

Abstract

BACKGROUND/AIMS:

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.

• Authors: J D Jia, M Bauer, J J Cho, M Ruehl, S Milani, G Boigk, E O Riecken, D Schuppan
• Journal: Journal of hepatology (J Hepatol) Vol. 35 Issue 3 Pg. 392-8 (Sep 2001) ISSN: 0168-8278 [Print] Netherlands
• PMID: 11592601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peptide Fragments
• Procollagen
• Silymarin
• Tissue Inhibitor of Metalloproteinase-1
• procollagen Type III-N-terminal peptide
• Collagen
• Collagenases
• Matrix Metalloproteinase 13
• Mmp13 protein, rat
• Matrix Metalloproteinase 3

Topics

• Animals
• Collagen (analysis)
• Collagenases (genetics)
• Down-Regulation
• Female
• Gene Expression Regulation (drug effects)
• Liver (chemistry, metabolism)
• Liver Cirrhosis, Biliary (drug therapy, metabolism)
• Matrix Metalloproteinase 13
• Matrix Metalloproteinase 3 (genetics)
• Peptide Fragments (analysis)
• Procollagen (analysis, genetics)
• Rats
• Rats, Wistar
• Silymarin (therapeutic use)
• Tissue Inhibitor of Metalloproteinase-1 (genetics)