Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.
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.
Kurosu
Hiroshi
H
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Choi
Mihwa
M
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Ogawa
Yasushi
Y
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Dickson
Addie S
AS
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Goetz
Regina
R
Department of Pharmacology, New York University School of Medicine, New York, New York 10016.
Eliseenkova
Anna V
AV
Department of Pharmacology, New York University School of Medicine, New York, New York 10016.
Mohammadi
Moosa
M
Department of Pharmacology, New York University School of Medicine, New York, New York 10016.
Rosenblatt
Kevin P
KP
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Kliewer
Steven A
SA
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Kuro-O
Makoto
M
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390. Electronic address: Makoto.Kuro-o@UTSouthwestern.edu.
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009928:Organ Specificity; D010766:Phosphorylation; D020033:Protein Isoforms; D051381:Rats; D015398:Signal Transduction
C117476:FGF19 protein, human; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C418622:Klb protein, mouse; D008565:Membrane Proteins; D020033:Protein Isoforms; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000090265:Klotho Proteins