Fisetin alleviates thioacetamide-induced hepatic fibrosis in rats by inhibiting Wnt/β-catenin signaling pathway

Abstract

Background

Liver fibrosis is a chronic wound-healing response to liver injury of various origins and represents a major health problem.

Objective

The current study endeavored to investigate the repressing effect of fisetin on hepatic fibrosis induced by thioacetamide (TAA) in rats.

Materials and methods

Rats were injected with TAA (200 mg/kg) intraperitoneally twice per week for 6 weeks to induce liver fibrosis. Fisetin (50 and 100 mg/kg/day) or silymarin (50 mg/kg/day) were given orally on a daily basis along with TAA. Liver function parameters, oxidative stress, inflammatory and fibrogenic biomarkers as well as wnt3a, β-catenin, glycogen synthase kinase 3 (GSK-3β) and cyclin D1 were estimated. Histoapthological and immunohistochemical examinations were performed.

Results

Fisetin restored normal liver functions, increased reduced glutathione (GSH) level and decreased malondialdehyde (MDA), as well as inflammatory biomarkers including; tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). Additionally, it lessened transforming growth factor β1 (TGF-β1), collagen I and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels as well as elevated matrix metalloproteinase-9 (MMP-9) hepatic content. Furthermore, fisetin significantly suppressed wnt3a gene expression associated with decreased β-catenin and increased GSK-3β levels. Moreover, fisetin decreased the progress of histologic hepatic fibroplasia and diminished hepatic expression of α-SMA and cyclin D1.

Conclusion

Fisetin curbed liver fibrosis and exhibited superior activity over silymarin through inhibition of hepatic stellate cells (HSCs) activation and proliferation via suppressing the Wnt/β-catenin pathway, modulating MMP-9 and TIMP-1, and inhibiting multiple profibrogenic factors, besides its antioxidant and anti-inflammatory effects. Therefore, fisetin is a promising therapeutic candidate for hepatic fibrosis.

Keywords:

• Fisetin
• fibrosis
• Wnt/β-catenin
• GSK-3β
• cyclin D1

Author contributions

Amany A. El-Fadaly and Abeer Salama designed the experiments, analyzed the data, performed the experiments, wrote and revised the manuscript. Mohamed F. Abdelhameed performed the experiments and revised the manuscript. Sahar S. Abd El-Rahman performed histopathological and immunohistopchemical examinations, analyzed the data, wrote and revised the manuscript. A. Ramadan, Wafaa El-Eraky and Nehal A. Afifi supervised and revised the manuscript.

Disclosure statement

The authors have declared that no conflict of interests exist between the authors.