Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen α1(I) and TIMP-1

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 α1(I), tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth factor (TGF) β1 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 α1(I), TIMP-1 and TGFβ1 (P<0.01). Silymarin downregulated elevated procollagen α1(I), TIMP-1 and TGFβ1 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 α1(I) and TIMP-1 most likely via downregulation of TGFβ1 mRNA in rats with biliary fibrosis. The serum procollagen type III propeptide level mirrors profibrogenic mRNA expression in the liver.