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Identification of growth differentiation factor 15 as a pro-fibrotic factor in mouse liver fibrosis progression
Peng Qi1, Ming-Ze Ma2, Jing-Hua Kuai3
1Department of Cardiac Surgery Intensive Care Unit, Qilu Hospital of Shandong University, Jinan, China.
Abstract:
The aim of this study was elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells (HSCs) of mice. We generated a GDF15-neutralizing antibody that can inhibit TGF-β1-induced activation of the TGF-β/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary HSCs from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-β pathway was detected using dual-luciferase reporter and Western blotting assays. The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-β pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary HSCs. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression. The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-β signalling.
Insights
Growth Differentiation Factor 15 (GDF15) inhibits liver fibrosis by delaying hepatic stellate cell activation. Blocking GDF15 with a neutralizing antibody shows therapeutic potential for liver fibrosis.
Area of Science:
- Hepatology
- Cell Biology
- Immunology
Background:
- Liver fibrosis is a significant health concern characterized by excessive extracellular matrix deposition.
- Hepatic stellate cells (HSCs) are key players in liver fibrosis progression.
- Growth Differentiation Factor 15 (GDF15) has emerged as a potential regulator in fibrotic diseases.
Purpose of the Study:
- To elucidate the inhibitory role of GDF15 in liver fibrosis.
- To investigate the mechanism of GDF15 activation in HSCs.
- To evaluate the therapeutic potential of blocking GDF15 in a mouse model of liver fibrosis.
Main Methods:
- Generation of a GDF15-neutralizing antibody.
- Induction of liver fibrosis in mice using carbon tetrachloride and thioacetamide.
- Isolation and culture of primary mouse HSCs.
- Assessment of liver fibrosis using Sirius Red and Masson staining.
- Evaluation of TGF-β pathway activation via dual-luciferase reporter and Western blotting assays.
Main Results:
- GDF15 expression was upregulated in cirrhotic liver tissue compared to normal tissue.
- Neutralization of GDF15 delayed HSC activation and ameliorated chemically induced liver fibrosis.
- GDF15-neutralizing antibody partially inhibited TGF-β pathway activation in primary HSCs.
Conclusions:
- GDF15 plays a crucial role in regulating HSC activation and liver fibrosis progression.
- Inhibition of GDF15 attenuates liver fibrosis and delays HSC activation, likely through modulation of the TGF-β signaling pathway.
- Targeting GDF15 represents a potential therapeutic strategy for liver fibrosis.
