Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor Isoforms determines metabolic activity of FGF19 and FGF21
Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor Isoforms determines metabolic activity of FGF19 and FGF21
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DOI：
10.1074/jbc.m704165200
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发表时间：
2007-09-14
影响因子：
4.8
通讯作者：
Kuro-o, Makoto
中科院分区：
文献类型：
--
作者：
Kurosu, Hiroshi;Choi, Mihwa;Kuro-o, Makoto
成纤维细胞生长因子（FGF）19配体亚家族FGF 19、FGF 21和FGF 23作为激素起作用，其通过激活FGF受体（FGFR 1 -4）来调节靶器官中的胆汁酸、脂肪酸、葡萄糖和磷酸盐代谢。我们证明了Klotho和β Klotho，与FGFR结合的同源单程跨膜蛋白，分别是FGF 23和FGF 21的代谢活性所需的。在这里，我们表明，与FGF 21一样，FGF 19也需要β Klotho。FGF 19和FGF 21都可以通过与β Klotho结合的FGFR 1 -3发出信号，并增加表达FGFR 1的脂肪细胞中的葡萄糖摄取。此外，FGF 19和FGF 21都与β Klotho-FGFR 4复合物结合;然而，只有FGF 19通过FGFR 4有效地发出信号。因此，FGF 19而非FGF 21激活主要表达FGFR 4的肝细胞中的FGF信号传导，并降低编码胆汁酸合成限速酶的CYP 7A 1的转录。我们得出结论，β Klotho的表达与特定的FGFR亚型结合，决定了FGF 19和FGF 21的组织特异性代谢活性。
The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors ( FGFR1-4). We demonstrated that Klotho and beta Klotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires beta Klotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by beta Klotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the beta Klotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of beta Klotho, in combination with particular FGFR isoforms,determines the tissue-specific metabolic activities of FGF19 and FGF21.