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Updated: May 1, 2026
Seven Steps to Stellate Cells
Published on: May 10, 2011
A Novel Anti-Fibrotic Role of G-Protein-Coupled Receptor 119 in Hepatic Stellate Cells
Jeongwoo Park1,2, Min Hoo Lee1, Hyun Young Kim1,3
1College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Abstract:
Liver fibrosis arises from chronic hepatic injury and remains a major clinical challenge due to the lack of effective therapies. Although G-protein-coupled receptor 119 (GPR119) has been explored as a metabolic target in type 2 diabetes, its role in liver fibrogenesis is not well understood. In this study, the protein and mRNA expression of GPR119 were detected in mouse primary hepatic stellate cells (HSCs) using immunostaining and reverse transcriptase-polymerase chain reaction. The anti-fibrotic activities of GPR119 agonists were assessed in primary HSCs, LX-2 cells, and a carbon tetrachloride (CCl₄)-induced mouse model of liver fibrosis. Treatment with the GPR119 agonists MBX-2982 and GSK1292263 inhibited HSC activation, suppressed transforming growth factor-β1 (TGFβ1)-induced Smad2/3 phosphorylation, and reduced the expression of fibrogenic genes. In vivo, oral administration of MBX-2982 attenuated collagen accumulation and decreased hepatic α-smooth muscle actin and TGFβ expression in CCl₄-treated mice. Mechanistically, MBX-2982 activated AMP-activated protein kinase (AMPK), and pharmacological inhibition of AMPK reversed its anti-fibrogenic effects. MBX-2982 further reduced Smad3 acetylation by disrupting the interaction between Smad3 and p300 and promoting AMPK-dependent proteasomal degradation of p300. These results identify GPR119 as a regulator of HSC activation and highlight GPR119 agonists as promising therapeutic candidates for liver fibrosis.
Insights
G-protein-coupled receptor 119 (GPR119) agonists show promise in treating liver fibrosis. These compounds inhibit hepatic stellate cell activation and reduce fibrotic markers by activating AMP-activated protein kinase (AMPK).
Area of Science:
- Hepatology and Pharmacology
- Cell Biology
- Molecular Medicine
Background:
- Liver fibrosis, a consequence of chronic liver injury, presents significant therapeutic challenges.
- The role of G-protein-coupled receptor 119 (GPR119) in liver fibrogenesis is largely unexplored, despite its known metabolic functions.
Purpose of the Study:
- To investigate the expression of GPR119 in hepatic stellate cells (HSCs).
- To evaluate the anti-fibrotic potential of GPR119 agonists in vitro and in vivo.
- To elucidate the underlying molecular mechanisms of GPR119-mediated anti-fibrotic effects.
Main Methods:
- GPR119 expression was analyzed in mouse primary HSCs via immunostaining and RT-PCR.
- Anti-fibrotic effects of GPR119 agonists (MBX-2982, GSK1292263) were tested in HSCs, LX-2 cells, and a carbon tetrachloride (CCl₄)-induced mouse model.
- Molecular mechanisms involving TGFβ1 signaling, AMPK activation, and Smad3 acetylation were investigated.
Main Results:
- GPR119 agonists inhibited HSC activation and suppressed TGFβ1-induced Smad2/3 phosphorylation.
- In vivo, MBX-2982 reduced collagen deposition and key fibrotic markers in CCl₄-treated mice.
- MBX-2982 activated AMPK, which was crucial for its anti-fibrotic activity, and reduced Smad3 acetylation by affecting p300 interactions.
Conclusions:
- GPR119 plays a significant role in regulating HSC activation.
- GPR119 agonists demonstrate potent anti-fibrotic properties.
- Targeting GPR119 via agonists represents a promising therapeutic strategy for liver fibrosis.
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