IL-1[Beta] inhibits [Beta]-Klotho expression and FGF19 signaling in hepatocytes

• Published in: American journal of physiology: endocrinology and metabolism 2016-02, Vol.310 (4), p.E289
• Main Authors: Zhao, Yueshui, Meng, Chenling, Wang, Yang, Huang, Huihui, Liu, Wenjing, Zhang, Jin-Fang, Zhao, Hui, Feng, Bo, Leung, Po Sing, Xia, Yin
• Format: Article
• Language: English
• Subjects: Cell growth; Cytokines; Metabolism; Protein expression; Signal transduction
• ISSN: 0193-1849; 1522-1555

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 β-Klotho to activate intracellular kinases, including Erk1/2. Studies have shown that proinflammatory cytokines such as TNFα impair FGF21 signaling in adipose cells by repressing β-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 β-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 TNFα, IL-1β, and IL-6, IL-1β drastically inhibited β-Klotho expression, whereas TNFα and IL-6 had no or minor effects. None of the three cytokines had any effects on FGFR4 expression. IL-1β directly inhibited β-Klotho transcription, and this inhibition required both the JNK and NF-...B pathways. In addition, IL-1β inhibited FGF19-induced Erk1/2 activation and cell proliferation. These results suggest that inflammation and IL-1β play an important role in regulating FGF19 signaling and function in the liver. (ProQuest: ... denotes formulae/symbols omitted.)