Tissue-specific expression of βklotho and Fibroblast Growth Factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21

Hiroshi Kurosu, Mihwa Choi, Yasushi Ogawa, Addie S. Dickson, Regina Goetz, Anna V. Eliseenkova, Moosa Mohammadi, Kevin P. Rosenblatt, Steven A. Kliewer, Makoto Kuro-O

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Abstract

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 βKlotho, 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 βKlotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-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 βKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.

Original languageEnglish (US)
Pages (from-to)26687-26695
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number37
DOIs
StatePublished - Sep 14 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kurosu, H., Choi, M., Ogawa, Y., Dickson, A. S., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Rosenblatt, K. P., Kliewer, S. A., & Kuro-O, M. (2007). Tissue-specific expression of βklotho and Fibroblast Growth Factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. Journal of Biological Chemistry, 282(37), 26687-26695. https://doi.org/10.1074/jbc.M704165200