Kurosu Hiroshi, Choi Mihwa, Ogawa Yasushi, Dickson Addie S, Goetz Regina, Eliseenkova Anna V, Mohammadi Moosa, Rosenblatt Kevin P, Kliewer Steven A, Kuro-O Makoto
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
J Biol Chem. 2007 Sep 14;282(37):26687-26695. doi: 10.1074/jbc.M704165200. Epub 2007 Jul 10.
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 betaKlotho, 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 betaKlotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the betaKlotho-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 betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.
成纤维细胞生长因子（FGF）19配体亚家族，即FGF19、FGF21和FGF23，作为激素发挥作用，通过激活成纤维细胞生长因子受体（FGFR1 - 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，与FGFRs结合的同源单次跨膜蛋白Klotho和βKlotho分别是FGF23和FGF21代谢活性所必需的。在这里我们表明，与FGF21一样，FGF19也需要βKlotho。FGF19和FGF21都可以通过与βKlotho结合的FGFR1 - 3发出信号，并增加表达FGFR1的脂肪细胞中的葡萄糖摄取。此外，FGF19和FGF21都与βKlotho - FGFR4复合物结合；然而，只有FGF19能通过FGFR4有效发出信号。因此，FGF19而非FGF21在主要表达FGFR4的肝细胞中激活FGF信号，并降低编码胆汁酸合成限速酶的CYP7A1的转录。我们得出结论，βKlotho的表达与特定的FGFR异构体相结合，决定了FGF19和FGF21的组织特异性代谢活性。
