期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：4
页码：1666-1671
DOI：10.1073/pnas.0913986107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{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)2D 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.
关键词：bile acid ; cholesterol ; mineral homeostasis ; Cyp genes ; energy source
