Conclusion
This study revealed a novel anti-inflammatory mechanism of FGF21 via inhibiting the hepatocyte-TLR4-IL-17A signaling in NASH-HCC models. The negative feedback loop on the hepatocyte-TLR4-IL-17A axis could be a potential anti-carcinogenetic mechanism for FGF21 to prevent NASH-HCC transition.
Methods
NASH models and NASH-HCC models were established in FGF21Knockout (KO) mice to evaluate NASH-HCC transition. IL-17A signaling was investigated in the isolated hepatic parenchymal cells, splenocytes, and hepatocyte and HCC cell lines.
Results
Lack of FGF21 caused significant up-regulation of the hepatocyte-derived IL-17A via Toll-like receptor 4 (TLR4) and NF-κB signaling. Restoration of FGF21 alleviated the high NAFLD activity score (NAS) and attenuated the TLR4-triggered hepatocyte-IL-17A expression. The HCC nodule number and tumor size were significantly alleviated by treatments of anti-IL-17A antibody.