Expression of fibroblast growth factor 21 and ß-Klotho regulates hepatic fibrosis through the nuclear factor-?B and c-Jun N-Terminal kinase pathways

Abstract

Background/Aims: Fibroblast growth factor (FGF) 21 is associated with hepatic inflammation and fibrosis. However, little is known regarding the effects of inflammation and fibrosis on the ß-Klotho and FGF21 pathway in the liver. Methods: Enrolled patients had biopsy-confirmed viral or alcoholic hepatitis. FGF19, FGF21 and ß-Klotho levels were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blotting. Furthermore, we explored the underlying mechanisms for this process by evaluating nuclear factor-?B (NF-?B) and c-Jun N-terminal kinase (JNK) pathway involvement in Huh-7 cells. Results: We observed that the FGF19 and FGF21 serum and mRNA levels in the biopsied liver tissue gradually increased and were correlated with fibrosis stage. Inflammatory markers (interleukin 1ß [IL-1ß], IL-6, and tumor necrosis factor-a) were positively correlated, while ß-Klotho expression was negatively correlated with the degree of fibrosis. In Huh-7 cells, IL-1ß increased FGF21 levels and decreased ß-Klotho levels. NF-?B and JNK inhibitors abolished the effect of IL-1ß on both FGF21 and ß-Klotho expression. FGF21 protected IL-1ß-induced growth retardation in Huh-7 cells. Conclusions: These results indicate that the inflammatory response during fibrogenesis increases FGF21 levels and suppresses ß-Klotho via the NF-?B and JNK pathway. In addition, FGF21 likely protects hepatocytes from hepatic inflammation and fibrosis.