Zhao Yueshui, Meng Chenling, Wang Yang, Huang Huihui, Liu Wenjing, Zhang Jin-Fang, Zhao Hui, Feng Bo, Leung Po Sing, Xia Yin
Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;
Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
Am J Physiol Endocrinol Metab. 2016 Feb 15;310(4):E289-300. doi: 10.1152/ajpendo.00356.2015. Epub 2015 Dec 15.
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-κB 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.
成纤维细胞生长因子（FGF）19是FGFs的FGF15/19亚家族成员，该亚家族包括FGF15/19、FGF21和FGF23。FGF19已被证明对肝脏代谢和再生有深远影响。FGF19与FGFR4及其共受体β-klotho结合以激活细胞内激酶，包括Erk1/2。研究表明，诸如TNFα等促炎细胞因子通过抑制β-klotho表达来损害脂肪细胞中的FGF21信号传导。然而，关于炎症对肝脏中FGF19信号通路的影响知之甚少。在本研究中，我们发现脂多糖（LPS）抑制小鼠肝脏中β-klotho和Fgfr4的表达，而LPS对Huh-7和HepG2细胞中的两种FGF19受体没有影响。在三种炎性细胞因子TNFα、IL-1β和IL-6中，IL-1β显著抑制β-klotho表达，而TNFα和IL-6没有影响或影响较小。这三种细胞因子均对FGFR4表达没有影响。IL-1β直接抑制β-klotho转录，并且这种抑制需要JNK和NF-κB途径。此外，IL-1β抑制FGF19诱导的Erk1/2激活和细胞增殖。这些结果表明炎症和IL-1β在调节肝脏中FGF19信号传导和功能方面发挥重要作用。
