Lack of FGF21 Promotes NASH-HCC Transition via Hepatocyte-TLR4-IL-17A Signaling

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Fibroblast growth factor (FGF21) holds great promise as an effective therapeutic means for treating nonalcoholic steatohepatitis (NASH) which is a potential precursor for hepatocellular carcinoma (HCC). We aimed to explore the potential mechanism(s) of FGF21 during NASH-HCC transition using a FGF21 knockout (KO) mouse model. 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. Down-regulated FGF21 but up-regulated IL-17A expression was also found in the HCC samples from our clinical patients and consistent with data analysis of Gene Expression Profiling Interactive Analysis (GEPIA). In conclusion, lack of FGF21 contributed to FFA mediated induction of hepatocyte-TLR4 signal to up-regulate IL-17A expression in hepatocytes. The potential anti-inflammatory effect of FGF21 could be through a negative feedback on the hepatocyte-TLR4 signaling to inhibit IL-17A production in the liver. 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. Funding: Research reported in this publication was supported partly by an Institutional Development Award (IDeA) from the NIGMS of the National Institutes of Health under grant number P20GM113226. Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The animal procedures were approved by the Institutional Animal Care and Use Committee of University of Louisville, which is certified by the American Association for Accreditation of Laboratory Animal Care. All the human sample collection procedures for this study were approved by the Institutional Review Board for Human Study at the University of Louisville.