Relevant use of Klotho in FGF19 subfamily signaling system in vivo.
Alpha-Klotho (alpha-Kl) and its homolog, beta-Klotho (beta-Kl) are key regulators of mineral homeostasis and bile acid/cholesterol metabolism, respectively. FGF15/ humanFGF19, FGF21, and FGF23, members of the FGF19 subfamily, are believed to act as circulating metabolic regulators. Analyses of functional interactions between alpha- and beta-Kl and FGF19 factors in wild-type, alpha-kl(-/-), and beta-kl(-/-) mice revealed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive/negative feedback actions of alpha-Kl, FGF23, and 1,25(OH)(2)D and an analogous regulatory network composed of beta-Kl, FGF15/humanFGF19, and bile acids that regulate bile acid/cholesterol metabolism. Contrary to in vitro data, beta-Kl is not essential for FGF21 signaling in adipose tissues in vivo, because (i) FGF21 signals are transduced in the absence of beta-Kl, (ii) FGF21 could not be precipitated by beta-Kl, and (iii) essential phenotypes in Fgf21(-/-) mice (decreased expressions of Hsl and Atgl in WAT) were not replicated in beta-kl(-/-) mice. These findings suggest the existence of Klotho-independent FGF21 signaling pathway(s) where undefined cofactors are involved. One-to-one functional interactions such as alpha-Klotho/FGF23, beta-Klotho/FGF15 (humanFGF19), and undefined cofactor/FGF21 would result in tissue-specific signal transduction of the FGF19 subfamily.
Tomiyama
Ken-ichi
K
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan.
Maeda
Ryota
R
Urakawa
Itaru
I
Yamazaki
Yuji
Y
Tanaka
Tomohiro
T
Ito
Shinji
S
Nabeshima
Yoko
Y
Tomita
Tsutomu
T
Odori
Shinji
S
Hosoda
Kiminori
K
Nakao
Kazuwa
K
Imura
Akihiro
A
Nabeshima
Yo-ichi
Y
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000172:deficiency / Q000378:metabolism*; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D014807:Vitamin D / Q000378:metabolism
D001647:Bile Acids and Salts; C000717428:Fgf23 protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins