The Wnt/β-Catenin Inhibitor HC-1 Suppresses Liver Fibrosis by Inhibiting Activated Hepatic Stellate Cells and Inducing Matrix Metalloproteinase-1.

Abstract

Background: Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) and is a risk factor for liver cancer. This study investigated the anti-fibrotic effect of the Wnt/β-catenin signalling inhibitor HC-1 in human hepatic stellate cells and a mouse liver fibrosis model.

Methods: The effects of HC-1 on Wnt/β-catenin and transforming growth factor (TGF)-β/Smad signalings were examined by a reporter assay. The effects of HC-1 on the mRNA expression of fibrogenesis- and fibrolysis-related genes were analysed after 24 and 48 h of exposure of HC-1. In the animal study, 30 male C57/BL6 mice treated with CCl₄ for 4 weeks were divided into three groups, namely vehicle, 8.7 mg/kg HC-1 and 17.4 mg/kg HC-1, respectively. Mice in the vehicle group underwent continued treatment with CCl₄, whereas those in the HC-1 groups were treated with both CCl₄ and HC-1 for another 4 weeks. The livers of mice were examined by histological and biochemical analyses.

Results: HC-1 decreased Wnt/β-catenin and TGF-β/Smad signallings. HC-1 potently reduced the mRNA expression of α-smooth muscle actin, collagen 1A1, TGF-β and lysyl oxidase. Conversely, HC-1 increased matrix metalloproteinase-1 expression in a concentration-dependent manner. In the animal model, HC-1 treatment significantly suppressed liver fibrosis in association with the inhibition of activated hepatic stellate cells. Although the Mmp-13, the murine functional homologue of MMP-1, was not increased, collagenase activity was increased in 8.7 mg/kg HC-1 group.

Conclusion: HC-1 exerts potent anti-fibrotic effects on liver fibrosis.