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Fibroblast Growth Factor 11 Inhibits Hepatitis B Virus Gene Expression Through FXRα Suppression
Mi So Seong1, Jeong Ah Jang1, Ye Rim Jeong1
1Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea.
Abstract:
Fibroblast growth factor 11 (FGF11) is a member of the intracellular FGF family, which shows different signal transmission compared with other FGF superfamily members. The molecular function of FGF11 is not clearly understood. In this study, we identified the inhibitory effect of FGF11 on hepatitis B virus (HBV) gene expression through transcriptional suppression. FGF11 decreased the mRNA and protein expression of HBV genes in liver cells. While the nuclear receptor FXRα1 increased HBV promoter transactivation, FGF11 decreased the FXRα-mediated gene induction of the HBV promoter by the FXRα agonist. Reduced endogenous levels of FXRα by siRNA and the dominant negative mutant protein (aa 1-187 without ligand binding domain) of FXRα expression indicated that HBV gene suppression by FGF11 is dependent on FXRα inhibition. In addition, FGF11 interacts with FXRα protein and reduces FXRα protein stability. These results indicate that FGF11 inhibits HBV replicative expression through the liver cell-specific transcription factor, FXRα, and suppresses HBV promoter activity. Our findings may contribute to the establishment of better regimens for the treatment of chronic HBV infections by including FGF11 to alter the bile acid mediated FXR pathway.
Insights
Fibroblast growth factor 11 (FGF11) inhibits hepatitis B virus (HBV) gene expression by suppressing the transcription factor FXRα. This discovery offers new therapeutic targets for chronic HBV infections.
Area of Science:
- Molecular biology
- Hepatology
- Virology
Background:
- Fibroblast growth factor 11 (FGF11) is an intracellular FGF family member with poorly understood functions.
- Hepatitis B virus (HBV) infection remains a significant global health concern, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of FGF11 in regulating hepatitis B virus (HBV) gene expression.
- To elucidate the molecular mechanism underlying FGF11's effect on HBV replication.
Main Methods:
- Assessing the impact of FGF11 on HBV gene mRNA and protein levels in liver cells.
- Investigating the interaction between FGF11 and the nuclear receptor FXRα (farnesoid X receptor alpha).
- Utilizing siRNA and dominant-negative mutants to confirm FXRα's role in FGF11-mediated suppression.
Main Results:
- FGF11 significantly decreased HBV gene expression at both mRNA and protein levels.
- FGF11 inhibited FXRα-mediated transactivation of the HBV promoter.
- FGF11 was found to interact with FXRα, reducing its protein stability and confirming FXRα dependence for HBV suppression.
- FGF11 suppresses HBV replication by inhibiting the liver cell-specific transcription factor FXRα.
Conclusions:
- FGF11 exerts an inhibitory effect on HBV gene expression through transcriptional suppression mediated by FXRα.
- FGF11's interaction with FXRα and subsequent reduction in its stability are key mechanisms for inhibiting HBV replication.
- Targeting the FGF11-FXRα pathway presents a potential novel therapeutic approach for chronic HBV infections, possibly by modulating the bile acid-mediated FXR pathway.
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