In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 4 ( 2010-01-26), p. 1666-1671
Abstract:
α-Klotho (α-Kl) and its homolog, β-Klotho (β-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 α- and β-Kl and FGF19 factors in wild-type, α-kl −/− , and β-kl −/− mice revealed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive/negative feedback actions of α-Kl, FGF23, and 1,25(OH) 2 D and an analogous regulatory network composed of β-Kl, FGF15/humanFGF19, and bile acids that regulate bile acid/cholesterol metabolism. Contrary to in vitro data, β-Kl is not essential for FGF21 signaling in adipose tissues in vivo, because ( i ) FGF21 signals are transduced in the absence of β-Kl, ( ii ) FGF21 could not be precipitated by β-Kl, and ( iii ) essential phenotypes in Fgf21 −/− mice (decreased expressions of Hsl and Atgl in WAT) were not replicated in β-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 α-Klotho/FGF23, β-Klotho/FGF15 (humanFGF19), and undefined cofactor/FGF21 would result in tissue-specific signal transduction of the FGF19 subfamily.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0913986107
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2010
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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