Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21*

By H. Kurosu, Mihwa Choi, Y. Ogawa, A. Dickson, R. Goetz, A. V. Eliseenkova, M. Mohammadi, K. Rosenblatt, S. Kliewer, M. Kuro-o. Journal of Biological Chemistry, 2007

717 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6264e38130fb7bfaf418f1bed4d49926341dc69b

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In Molecular Biology

1. M. Mohammadi
2. M. Kuro-o
3. N. Itoh
4. D. Ornitz
5. Bart Staels
6. D. Mangelsdorf
7. A. Beenken

Citations in the corpus

• Role of bile acids and bile acid receptors in metabolic regulation. (2009, background): “More recently, FGF19 has been shown to increase glucose uptake in 3T3-L1 adipocytes in vitro (164).”
• Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. (2011, background): “The phenotypes of Klotho knockout mice overlap those of Fgfr4 knockout mice and Fgf15/19 knockout mice (28, 29).”
• Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. (2010, background): “That FGF19 can signal through Lctl-FGFR complexes is intriguing in light of the known effects of FGF15/19 in tissues in which Lctl is expressed, namely brown adipose tissue and eye.”