IL-1β inhibits β-Klotho expression and FGF19 signaling in hepatocytes

Fibroblast growth factor (FGF) 19 is a member of the FGF15/19 subfamily of FGFs that includes FGF15/19, FGF21, and FGF23. FGF19 has been shown to have profound effects on liver metabolism and regeneration. FGF19 binds to FGFR4 and its coreceptor beta-Klotho to activate intracellular kinases, including Erk1/2. Studies have shown that proinflammatory cytokines such as TNF alpha impair FGF21 signaling in adipose cells by repressing beta-Klotho expression. However, little is known about the effects of inflammation on the FGF19 pathway in the liver. In the present study, we found that lipopolysaccharide (LPS) inhibited beta-Klotho and Fgfr4 expression in livers in mice, whereas LPS had no effects on the two FGF19 receptors in Huh-7 and HepG2 cells. Of the three inflammatory cytokines TNF alpha, IL-1 beta, and IL-6, IL-1 beta drastically inhibited beta-Klotho expression, whereas TNF alpha and IL-6 had no or minor effects. None of the three cytokines had any effects on FGFR4 expression. IL-1 beta directly inhibited beta-Klotho transcription, and this inhibition required both the JNK and NF-kappa B pathways. In addition, IL-1 beta inhibited FGF19-induced Erk1/2 activation and cell proliferation. These results suggest that inflammation and IL-1 beta play an important role in regulating FGF19 signaling and function in the liver.