Abstract
Background and Aims: Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, which occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. Activated hepatic perivascular stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines, such as TGF-β1. The inhibition of TGF-β1 function or synthesis is a major target for the development of antifibrotic therapies. Our previous study showed that the water and ethanol extracts of Graptopetalum paraguayense (GP), a Chinese herbal medicine, can prevent dimethylnitrosamine (DMN)-induced hepatic inflammation and fibrosis in rats. Methods: We used rat hepatic stellate HSC-T6 cells and a diethylnitrosamine (DEN)-induced rat liver injury model to test the potential mechanism of GP extracts and its fraction, HH-F3. Results: We demonstrated that GP extracts and HH-F3 downregulated the expression levels of extracellular matrix (ECM) proteins and inhibited the proliferation and migration via suppression of the TGF-β1 pathway in rat hepatic stellate HSC-T6 cells. Moreover, the HH-F3 fraction decreased hepatic collagen content and reduced plasma AST, ALT, and γ-GT activities in a DEN-induced rat liver injury model, suggesting that GP/HH-F3 has hepatoprotective effects against DEN-induced liver fibrosis. Conclusion: These findings indicate that GP/HH-F3 may be a potential therapeutic agent for the treatment of liver fibrosis. The inhibition of TGF-β-mediated fibrogenesis may be a central mechanism by which GP/HH-F3 protects the liver from injury.
Highlights
Liver fibrosis results from chronic damage to the liver in conjunction with the accumulation of an extracellular matrix (ECM), which includes four large families of macromolecules: glycoproteins, collagens, proteoglycans, and carbohydrate [1,2]
We previously showed that Graptopetalum paraguayense (GP) extracts could inhibit liver cancer proliferation and have synergistic effects with sorafenib on hepatocellular carcinoma (HCC) cells [16,17]
The results demonstrated tha4t TGF-β1 treatment alone significantly stimulated the proliferation of hepatic stellate cells (HSCs)-T6 cells
Summary
Liver fibrosis results from chronic damage to the liver in conjunction with the accumulation of an extracellular matrix (ECM), which includes four large families of macromolecules: glycoproteins, collagens, proteoglycans, and carbohydrate [1,2]. A key step in the pathogenesis of liver fibrosis is the activation of hepatic stellate cells (HSCs) in response to chronic liver injury. This activation process is characterized by a phenotypic switch from a quiescent vitamin A-rich phenotype to a myofibroblastic fibrogenic phenotype; this switch is mainly due to the effects of several mediators, such as reactive oxygen species (ROS), lipid peroxidation (LPO) products, and fibrogenic cytokines such as transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF). A partially purified 30% DMSO GP extract, HH-F3, significantly inhibited the TGF-β-induced proliferation and migration of activated HSCs. HH-F3 alleviated liver injury in a DEN-induced mouse model
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