Hesperetin Mitigates Bile Duct Ligation-Induced Liver Fibrosis by Inhibiting Extracellular Matrix and Cell Apoptosis via the TGF-β1/Smad Pathway

Background: Hesperetin, a natural component of citrus fruits, is indicated to have beneficial anti-inflammatory effects on injury and various cancers as a transforming growth factor beta (TGF-β) inhibitor. However, little evidence associates hesperetin with liver fibrosis. Objective: Work from our laboratory aims at finding the mechanism by which hesperetin attenuates liver fibrosis. Methods: Bile duct ligation (BDL) was used to induce liver fibrosis in mice and the findings were determined using enzyme-linked immunosorbent assay, quantitative realtime polymerase chain reaction, western blotting and immunohistochemical staining. Results: Data from Immunohistochemical staining and injury score indicated that pathological lesions were reduced by hesperetin treatment. Decreasing levels of several serum parameters including cytokines tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), liver enzyme alanine aminotransferase (ALT) and aspartate aminotransferase (AST), fibrosis indicators laminin (LN), hyaluronic acid (HA) and hydroxylproline (Hyp) suggested similar results to the immunohistochemical. In addition, our data verified hesperetin could suppress the formation of extracellular matrix and hepatocyte apoptosis in vitro, together with promoting hepatic stellate cell death in vivo, which was considered to be associated with the inhibition of TGF-β1/Smad pathways. Conclusion: In the present study, the favorable role of hesperetin extracted from citrus peels was verified to prevent the progression of BDL-induced liver fibrosis via inhibiting TGF-β1/Smad pathway-mediated extracellular matrix progression and apoptosis.