Effects of geniposide on hepatocytes undergoing epithelial-mesenchymal transition in hepatic fibrosis by targeting TGFβ/Smad and ERK-MAPK signaling pathways

Liver fibrosis results from increased deposition of type-I collagen within the hepatic extracellular space and constitutes a common cardinal signature in all forms of liver injury, regardless of etiology. Transforming growth factor β1 (TGF-β1) plays a crucial role in the pathogenesis of liver fibrosis. Geniposide is recognized as being useful against hyperlipidemia and fatty liver. However, its cellular mechanism and anti-fibrotic effect in TGF-β1-induced hepatocytes have not been explored. In the present study, we investigated its anti-epithelial-mesenchymal transition (EMT) mechanism by examining the effect of geniposide on TGF-β1-induced hepatocytes. The effect of geniposide on TGF-β1-induced AML12 cells was assessed using Western blotting, quantitative real-time PCR, immunofluorescence staining and DNA binding activity. We found that geniposide significantly inhibited TGF-β1-induced mRNA and protein expression of type-I collagen. Cells treated concurrently with TGF-β1 and geniposide retained high levels of localized E-cadherin expression with no increase in vimentin. Treatment with geniposide almost completely blocked the phosphorylation of Smad2/3, extracellular signal-regulated kinase (ERK) and Akt in AML12 cells. Taken together, these results suggest that geniposide may suppress TGF-β1-induced EMT in hepatic fibrosis by inhibiting the TGFβ/Smad and ERK-mitogen-activated protein kinase (MAPK) signaling pathways. Our results may help researchers better understand the pathogenesis of liver fibrosis so they can develop novel therapeutic strategies for treatment of liver diseases.