Relevant use of Klotho in FGF19 subfamily signaling system in vivo
Relevant use of Klotho in FGF19 subfamily signaling system in vivo
复制标题
DOI：
10.1073/pnas.0913986107
复制
发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Nabeshima, Yo-ichi
中科院分区：
文献类型：
--
作者：
Tomiyama, Ken-ichi;Maeda, Ryota;Nabeshima, Yo-ichi
α-Klotho（α-K1）及其同系物β-Klotho（β-K1）分别是矿物质稳态和胆汁酸/胆固醇代谢的关键调节剂。FGF 15/人FGF 19、FGF 21和FGF 23（FGF 19亚家族的成员）被认为充当循环代谢调节剂。对野生型、α-kl（-/-）和β-kl（-/-）小鼠中α-和β-Kl与FGF 19因子之间的功能相互作用的分析揭示了矿物质稳态的综合调节方案，其涉及α-Kl、FGF 23和1，25（OH）（2）D的相互调节的正/负反馈作用以及由β-Kl、FGF 15/人FGF 19、和调节胆汁酸/胆固醇代谢的胆汁酸。与体外数据相反，β-Kl对于体内脂肪组织中的FGF 21信号传导不是必需的，因为（i）FGF 21信号在不存在β-Kl的情况下转导，（ii）FGF 21不能被β-Kl沉淀，和（iii）Fgf 21（-/-）小鼠中的必需表型（WAT中Hsl和Atgl的表达降低）在β-kl（-/-）小鼠中没有复制。这些发现表明存在Klotho非依赖性FGF 21信号传导途径，其中涉及未定义的辅因子。一对一的功能相互作用如α-Klotho/FGF 23、β-Klotho/FGF 15（人FGF 19）和未定义的辅因子/FGF 21将导致FGF 19亚家族的组织特异性信号转导。
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.